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Medicine Monographs 

1 MEDICINE MONOGRAPHS are comprehensive 

'! reviews that adequately discuss a disease, certain 

aspects of a disease, or subjects that allow a better 
|, comprehension of disease processes. 


if MEDICINE MONOGRAPHS will enable the teacher, 

If the clinician, and the laboratory worker to have avatta- 

I ble, in convenient and readable form, critical digests of 

>the recent views on general medicine, neurology and 

MEDICINE MONOGRAPHS originally appeared 
in MEDICINE, a quarterly periodical edited by 
David L. Edsatt, Harvard Medical School; Associate 
i Editor, Alan M. Chesney, Johns Hopkins Hospital. 




>* ' 






Department of Pharmacology 
Johis Hopktns University 



Department of Pharmacology 
University of Pennsylvania 







Departments of Pharmacology, Johns Hopkins University and University of Pennsylvania 


L Introduction 2 

Historical 4 

n. Pharmacognosy and chemistry 7 

1. Botany 7 

2. Properties of ephedrine 9 

a. Isolation 9 

b. Yield 9 

c. Recent commercial development 11 

d. Physical and chemical characteristics 12 

e. Structure and isomerism 13 

f . Other alkaloids occurring in Ma Huang 14 

g. Synthesis of ephedrine 14 

in. Pharmacological action 15 

1. Action on lower forma of life 16 

2. Actions on the circulation 17 

a. Effect upon blood pressure 17 

b. Action on heart 23 

c. Action on blood vessels 29 

3. Action on respiration 32 

4. Action on smooth muscle 33 

a. Pupil 33 

b. Gastro-intestinal tract 35 

c. Uterus 39 

d. Urinary tract 39 

e. Bronchi 40 

5. Action on secretions 40 

a. Saliva 40 

b. Gastric secretion 41 

c. Pancreatic secretion 41 

d. Intestinal secretion 41 

e. Bile 41 

f. Sweat 41 

g. Lymph 42 

h. Urine 42 

6. Action on blood 42 

a. Blood cells 42 

b. Blood chemistry 43 



7. Action on metabolism 44 

a. Metabolic rate 44 

b. Gaseous exchange 44 

c. Body temperature 44 

8. Action on central nervous system 45 

9. Action on peripheral nerves and voluritary muscles 45 

10. Mode of action 46 

a. Circulatory responses 48 

b. Effects upon smooth muscle 51 

11. Absorption and excretion 59 

12. Toxicity 59 

a. Minimal lethal dose 59 

b. Toxic symptomatology 61 

c. Repeated administration 61 

IV. Clinical applications 62 

1. Methods of administration and dosage 62 

2. Side effects 63 

V. Therapeutic uses 65 

1. In asthma 65 

2. In hay fever 69 

3. In bronchitis and emphysema 70 

4. In whooping cough 70 

5. In spinal anesthesia 71 

6. In hypotension 72 

7. In shock 74 

8. In Adams-Stokes' syndrome 75 

9. As a nasal astringent 76 

10. As a mydriatic 77 

11. As an antidote for narcotic drugs 79 

12. In dermatology 80 

a. In urticaria 80 

b. In dermatitis medicamentosa 81 

c. In leprosy 81 

13. In dysmenorrhea 82 

VI. Action of synthetic ephedrine and compounds optically isomeric with or related 

to ephedrine 82 

1. Synthetic or tW-ephedrine 82 

2. Pseudoephedrine 4. 85 

3. Other optical isomers of ephedrine 87 

4. Compounds related to ephedrine 88 

VTI. Summary 93 

References 94 


The rise of ephedrine from obscurity to its present state of wide- 
spread popularity, within less than five years, involves a variety of 
features of unusual interest. Much of the initial enthusiasm for the 


drug was doubtless due to the somewhat dramatic circumstance that 
the traditional faith of the Chinese in one of their ancient remedies 
was about to be justified by Western science. While ephedrine has 
recently found a real place in therapeutics, the drug was known to 
experimenters and clinicians for some thirty years before its possi- 
bilities were appreciated. The reason for this tardy recognition 
was simply the failure of the original investigators to use any but toxic 
doses in their animal experiments a circumstance which illustrates 
the readiness with which an initial misconception may be propagated 
and may influence the subsequent fate of a new remedy. The history 
of ephedrine is therefore of more than usual interest. 

Apart from the historical aspect, ephedrine has been the object of 
a great deal of investigation on the part of laboratory workers and 
clinicians. The result has been not only the discovery of unantici- 
pated uses for the drug but of greater ultimate importance a 
renewal of interest in the problem of the relation of chemical com- 
position to physiological actions, and the direction of attention to the 
incompleteness of our knowledge concerning the mode of action of 
sympathomimetic drugs (i.e , those which produce effects similar to 
the result of excitation of sympathetic innervations). It is now quite 
certain that ephedrine, in spite of its present popularity, is far from 
ideal in certain respects. In the search for other remedies of this sort 
important progress has already been made, and undoubtedly much 
more lies in the immediate future. For the benefit of those concerned in 
such work, and of the clinicians in whose hands rests the final decision 
concerning the validity of laboratory experimentation with agents of 
possible therapeutic importance, a compilation of the literature 
dealing with ephedrine should serve a useful purpose. For if ephedrine 
is not the only agent of this sort to have been introduced into thera- 
peutics since epinephrine was discovered, it has certainly been the 
object of more investigation than any other. In spite of this, the 
v literature is full of disagreements and unjustified assumptions with 
Irespect to the fundamental features in the action of the drug, though 
|the_ clinical results are quite uniform in indicating that it produces 
'i effects that are of the same nature as those of ep^ejDhrine. It is 
Inevitable that workers with other substances of tlnTsdrt will be con- 
fronted with the same difficulties. These can be obviated, to some 


extent at least, if it is generally realized that a drug can be sympa- 
thomimetic, in the original sense of the term, without duplicating all 
of the effects of epinephrine. 


As is generally known, ephedrine is an alkaloidal active principle 
obtained from a Chinese herb which, under the name of Ma Huang, 
has been used by native physicians for some 5000 years. It was one 
of the drugs which is said to have been tasted by the Emperor Shen 
Nung, who placed it in the "medium class." It is mentioned in the 
Pentsao Kang Mu, the Chinese dispensatory, written in 1596 by 
Shih-Cheng Li. According to this authority Ma Huang is of value as 
a circulatory stimulant, diaphoretic, antipyretic, sedative in cough, 
and it is an ingredient of many famous prescriptions. An English 
translation of the ancient Chinese records can be found in the paper 
by Hagerty and Woo. 

Plants similar to, if not identical with Ma Huang have been em- 
ployed as medicines since remote antiquity in other parts of the world. 
Thus, it is said (Berendes) that Greek physicians employed plants of 
the same genus (Ephedra) as Ma Huang, and that the Hippuris of 
Dioscorides (about 50 A.D.) was E. fragUis var. graeca. The top of 
this plant was used as an astringent; taken with wine it was said to 
produce diuresis and to cure dysentery, and both root and top were 
reputed to be useful in the treatment of cough, orthopnea, and internal 
rupture (Berendes). 

In Russia Ephedras have been in medical use since olden times. In 
the 19th century decoctions of E. wlgaris, together with milk and 
butter, were recommended in the treatment of rheumatism and were 
regarded as a specific remedy for syphilis and gout, the latter virtue 
being attributed to the twigs and roots of the plant. The sap and 
candied fruits were used in the treatment of respiratory disorders. 
A peasant named Kusmitsch effected such marvelous cures with 
decoctions of Ephedra that he won a wide reputation, and Bechtin 
(1891) reported very striking results with decoctions of E. vulgaris in 
patients with rheumatism. Sassetsky and Lewaschew, however, were 
unable to confirm these results (Grahe). 

In India the dried branches of E. pachydada, or E. intermedia, 


/ are thought to possess medicinal value, but they are chiefly used in 

I religious (Parsi) ceremonials. It is also said that this plant, mixed 

1 with milk and honey and allowed to ferment, was the "soma" of 

the Vedas, which was used to induce an exhilarating intoxication. 

'; , Incidentally, this appears to be the only instance of employment of an 

\ Ephedra for the purpose of pleasurable intoxication, and it is possible 

that the effects were due to alcohol in this case. 

In America a number of Ephedra plants were used by the Indians 
for various purposes. E. antisyphilitica, E. caUfornica, and E. 
nevadensis were regarded as valuable in the treatment of syphilis and 
gonorrhoea, and were used as local applications as well as by internal 
administration. The Coahuila Indians made a cooling beverage 
from E. nevadensis, and the Panamint Indians made bread from the 
ground roasted seeds of the same plant. The Indians and Spaniards 
used decoctions of E. catifomica as a tonic and blood purifier, and 
E. trifurca was regarded as an excellent remedy for nephritis. In 
Mexico, E. aspera is still used occasionally in the treatment of pneu- 
monia, and in Zacatecas E. pedunculata is highly esteemed as a remedy 
for pleurisy and pneumonia. 

It appears, therefore, that the Epkedras have long been utilized as 
empirical remedies hi many discontiguous parts of the world. On 
the whole, they seem to have enjoyed a reputation for two different 
sorts of usefulness first, in the treatment of venereal diseases, and 
second, in treating disorders of the respiratory system. 

The development of a useful modern drug out of these ancient 
remedies has centered upon the Chinese plant Ma Huang and, as is 
usually the case, has followed as a natural consequence of the isolation 
of an active principle. Pioneer work along these lines was done 
wholly by the Japanese, whose interest in Chinese drugs was naturally 
greater than that of the Western world because most of their empirical 
materia medica including Ma Huang was derived from the ancient 
culture of China. An active principle was first isolated from Ma 
Huang in 18&5 by G. Yamanashi, who obtained a crystalline though 
impure substance. After his death the study was continued by Nagai, 
with the assistance of Y. Hori, who obtained the alkaloid in pure form 
(1887). The same compound was obtained in Germany by E. Merck 
in 1888. The name ephedrine was first applied to this substance by 


Nagai, though the name had already been coined in 1875 by Loew 
for the tannin which he had prepared from E. antisypMHtica. The 
name ephedrine is now used only in the sense in which Nagai em- 
pjoyed it, viz., to designate an alkaloidal active principle of Ma 
Huang and other Ephedras. 

Nagai's ephedrine was subjected to physiological investigations by 
Miura (1887). This study disclosed the toxic effects of large doses 
upon the circulation and demonstrated the mydriatic action of the 
drug. As a result it was introduced to Western medicine as a new 
mydriatic, but its vogue was limited and brief. Apparently it was 
not utilized for other purposes and was regarded as a very toxic sub- 
stance. It is interesting to note that ephedrine, which has recently 
attained popularity as a substitute for or adjuvant to epinephrine, 
was available in pure form five years before the actions of suprarenal 
extracts were first worked out completely and more than twelve years 
before epinephrine, the active principle of suprarenal medulla, was 
first isolated. 

Subsequently interest in ephedrine was, for many years, almost 
wholly limited to analyses of its chemical composition and to attempts 
at synthesizing it (see below). Six years before our work was under- 
taken the Japanese investigators Amatsu and Kubota (1917) demon- 
strated the essentially sympathomimetic (epinephrine-like) effects of 
ephedrine, and other workers Hirose, and To also contributed to 
,the same conclusion. These publications attracted little attention in 
America and Europe, but as a result of their work the Japanese became 
so convinced of the value of ephedrine in the treatment of one condi- 
tion that is relieved by epinephrine namely, asthma that an 
fephedrine-containing preparation was put on the market in Mukden 
[.under the name of Asthmatol. No publication was made of the 
nfesults obtained with this product and when the question of the 
therapeutic possibilities of ephedrine was reopened in 1923 this 
development was unknown to the Western world (and to the authors). 
It is proper, however, that the Japanese scientists should be given due 
credit for having been the first to appreciate the usefulness of ephe- 
drine for purposes other than ophthalmologic. 

The work done by the authors upon this subject was the result of a 
suggestion made by a Chinese druggist, in response to an inquiry 


concerning native drugs which might be expected to possess real 
actions. Among others, Ma Huang was mentioned, and a small 
supply was obtained for future investigation. In the autumn of 1923 
a decoction made from this material was injected into a vein of an 
anesthetized dog remaining alive at the end of a student exercise. 
The consequent circulatory effect was the one now familiar as that of 
ephedrine, and attention was concentrated upon this promising drug. 
A crystalline alkaloid was readily isolated from it, and further experi- 
ments demonstrated that this was the active principle, that it possessed 
epinephrine-like effects, that it was of comparatively low toxicity, 
and that it was effectively absorbed from the gastro-intestinal tracts of 
dogs and men. A search of the literature disclosed the identity of this 
substance as ephedrine. Clinical trial of the drug was limited by the 
small quantity of ephedrine available at the time. As soon as a 
sufficient supply was prepared it was submitted to Dr. T. G. Miller, 
of the University of Pennsylvania, and to Dr. L. G. Rowntree, of the 
Mayo Clinic, for clinical experiments. The results being favorable, 
ephedrine was made available to clinicians in general, as rapidly as 
possible. In 1926 ephedrine was submitted to the Council of Pharmacy 
and Chemistry of the American Medical Association, and was sub- 
sequently approved by it. The drug is now prepared by a number of 
manufacturers and is quite generally obtainable. 

One of the interesting aspects of the usefulness of ephedrine, as 
established by modern clinicians and experimenters, is that it justifies 
the Chinese tradition concerning Ma Huang in many respects. 


1. Botany 

Ephedrine occurs in certain plants of the genus Ephedra (family 
Ephedraceae) which includes a large number of species (35, according 
to Engler and Prantl, 1926 ; 45, according to the Index Kewensis, 1895- 
1920). These are distributed throughout the temperate and sub- 
tropical regions of Europe, Asia, and America. They are found hi an 
area extending from the middle Amur region through central Asia, 
including its deserts and covering China and Arabia, to the Mediter- 
ranean and even to the Canary Islands (Engler and Prantl), as well as 


Siberia, Hungary, the Carpathian Mountains, the Western Alps, and 
Western France. In the Americas they grow along the Rocky Moun- 
tains as far south as New Mexico, from Bolivia to Patagonia, and from 
Paraguay to the Atlantic Ocean. 

Only a few of these Ephedras contain ephedrine. In China ephe- 
drine-bearing plants are found in the Tai-hung Mountains, which are 
the site of the Great Wall in Chihli Province. They also occur in 
Shansi, Shensi, Kansu, Honan, and Hupeh Provinces (Read and 
associates, 1928). They are also found in Northern Chosen (Korea) 
and in Akita Prefecture in Japan. In India and Tibet they occur 
along the Himalaya Mountains (Chopra and associates). 

The actual identification of Ma Huang has been somewhat uncer- 
tain. It was formerly classified as E. vulgaris var. helvetica (Nagai; 
Botanical Nomenclature, etc.), but this name appears to be obsolete. 
Cowdry (1922) identified Ma Huang as E. equisetina, and this is the 
name recognized by the Council on Pharmacy and Chemistry of the 
American Medical Association for the plant from which ephedrine is 
obtained. Holmes (1926) suggested that Ma Huang is E. intermedia 
var. tibetica, while Stapf (1927) gave a provisional new name of E. 
simica to specimens submitted by Read and by Parke, Davis & Com- 
pany. Liu and Read (1929) identified another species, E. distachya, 
which is found in Western Chihli and is also known as Ma Huang. 
This statement needs confirmation. At present it appears that Ma 
Huang, from which most of the present supply of ephedrine is ob- 
tained, is E. sinica or E. equisetina (Small and Short). It has been 
shown recently by Chopra and his coworkers (1928), that ephe- 
drine also occurs in the Indian species, E. vulgaris, E. pachyclada or 
intermedia, and E. intermedia var. helvetica. Their results have been 
confirmed by Read and Feng (1928). 

These are the principal natural sources of ephedrine at present, 
though ephedrine is also found in plants growing in Southern Europe, 
in Northern China and in Japan. Other Ephedras have been examined 
but they contained no alkaloid, or only the isomeric pseudoephedrine, 
which is distinctly less useful than ephedrine. The American ^species 
E. trifurca, E. nevadensis, E. calif arnica, and E. viridis were examined by 
Nielson, McCausland, and Spruth, and found to contain no alkaloid. 
Terry obtained the same negative result with E. nevadensis. Clark 

1 1 



and Groff reported the presence of pressor siibstan^es~"iineXEfacts 
of jE. californica and E. nevadensis, though no try& 
substance could be isolated. Their results were not substantiated by 
De Eds and Butt or by Read and Feng. Black and Kelly found only 
pseudoephedrine in E. alata, collected in Morocco. None of the 
American Ephedras have been shown to contain ephedrine, and upon 
transplanting the Swiss E. vulgaris (E. distachya), which is believed 
to yield ephedrine, to this country, no alkaloid was found in it after 
the first year of growth (Nielsen and McCausland, 1928). 

2. Properties of ephedrine 

a. Isolation. Ephedrine, having the solubility reactions of a 
typical alkaloid, is very easily separated from an extract of the plant 
The following procedure has been found satisfactory. 

The powdered crude drug is extracted with 60 per cent alcohol, 
the extract concentrated and treated with strong ammonum hydroxide 
or sodium carbonate. This causes precipitation, and filtration is 
necessary: ephedrine is present in both precipitate and filtrate, so that 
both must be dealt with. The akaloid is extracted from them by 
means of chloroform or ether. Upon removal of the solvent the 
residue is neutralized with dilute HC1 or H 2 S04, thus forming the cor- 
responding salt of the alkaloid, which is finally purified and repeatedly 
crystallized from absolute alcohol. It is obvious that a chemical 
assay of ephedra-bearing plants is readily carried out, and this is 
fortunate because no satisfactory bio-assay has been developed. 

b. Yield. Different investigators have obtained widely divergent 
results, even with the same plant, as shown in table 1. Generally 
speaking, the earlier workers obtained lower yields than the more 
recent ones, most of whom have succeeded in isolating more than 1 
per cent of total alkaloids from the Chinese plants: of this 80 per 
cent or more is ephedrine. The Indian species E. pachydada and 
E. intermedia var. tibetica have a distinctly lower ephedrine content 
than the Chinese. 

Read and his associates in Peiping have made careful studies of this 
question. They (Feng and Read) find that the low yield of ephedrine 
obtained by previous workers was due to incomplete aJkalmization of 
the percolate before extraction with chloroform or ether, and em- 



phasize the necessity of adding a large excess of ammonium hydroxide 
in order to liberate the alkaloids completely. They have also studied 
the variations in yield of ephedrine from different parts of the plant 
and at different seasons of the year (Feng and Read, 1928). They 
find progressive increase in total ephedrine content from spring to 
autumn, the maximum being attained just before the frosts. The 
old Chinese custom of collecting the plant in the autumn therefore 
appears to be based upon sound observation. During the flowering 
season the male plant contains more alkaloid than the female, the 

Assay of Ephedras reported by different workers 



Masucci and Suto 

Schoetzon and Needham 

Neilson, McCaualand and 

Feng and Read 
Feng and Read 
Chopra, Dikshit and Pillai 
Read and Feng 
Chopra, Dikshit and Pillai 
Read and Feng 
Chopra, Dikshit and Pillai 

difference being greatest in May. After the fruiting season the alka- 
loid content is practically equal in plants of both sexes. With respect 
to the distribution of alkaloid in different parts of the plant, these 
investigators find (in E. equisetina) that the nodes contain much less 
ephedrine than the internodes, and that the root, berries, seeds, and 
woody stalks contain none at all. Similar conclusions were reached 
by Chopra and his associates'with respect to Indian species of Ephedra. 
The special tissue of the plant stem which is concerned in manu- 
facturing or storing ephedrine has not been determined. Nothing is 
known about the manner in which it is synthesized by the plant or 


Ma Huang 


31-0 40 

KPH jcngTtinc. 

Ma Huar>g 

02-0 09 

Ma Huang 


Ma Huang 

0.40-0 86 

Ma Huang 

20-0 90 

Ma H^ang , . . , 

64-1 43 

E. Eguisetina. 

1 75 


B. Sinica, 

1 32 


E. vulgaris 

1 02-1 27 


E. vulgaris 

1.65-1 70 


E pachyclada 

1 8 


E. pachyclada 
E. intermedia var. Tibetica 

1 15 
0.25-0 60 



the circumstances under which it may be transformed into its optical 
isomer, pseudoephedrine, or demethylated or methylated within the 
plant. A study of the climatic and soil conditions under which the 
plant would produce its maximum yield of ephedrine could be made 
with profit. 

c. Recent commercial development. The recent popularity of ephe- 
drine has led to the development of a considerable industry in China. 
Ephedrine has been upon the market for more than 30 years. It has 
been listed in E. Merck's Index since 1896. Japanese manu- 
facturers (Dainihon Seiyaku Kabushiki Kaisha, of Osaka, later suc- 
ceeded by the firms of Tanabe and Takeda) also prepared ephedrine, 
and the proprietary preparation Asthmatol contained ephedrine. 
As far as is known to the reviewers, these were the only commercial 
supplies of ephedrine in the world prior to 1924, and the quantities 
produced were relatively insignificant, since the drug was scarcely 
used at all except for chemical investigations. According to Mr. G. 
Woodard, Assistant Trade Commissioner of the United States at 
Shanghai, Ma Huang was exported almost exclusively through 
German firms for the past 30 years. Read (1928) states that Ma 
Huang was probably never exported from Tientsin prior to August, 
1926, but from this time the trade developed rapidly. By the end of 
1926 the exports from Tientsin alone, and to the United States alone, 
amounted to 224,058 pounds, valued at $17,753, during 1927 they were 
622,060 pounds and $64,840, and for the first 11 months of 1928 they 
were 1,003,700 pounds and $69,300. (The figures for 1926 and 1927 are 
cited by Read; those for 1928 were furnished by Mr. A. G. Ward, 
U. S. Vice-Consul at Tientsin.) In addition to the crude drug, 
ephedrine hydrochloride, prepared by the Department of Chemical 
Products of Peiping Union Medical College, was exported through 
Tientsin as follows: in 1926, 12$ pounds, valued at U. S. $3,612; 
in 1927, 23 pounds and $7,490; in 1928 (to December 1) 20 pounds and 
$3,688. Ma Huang has also been exported from Shanghai and 
Hankow, but the quantities concerned are unknown to the writers: 
it is certain that the above figures underestimate the Chinese trade 
in this drug. Furthermore, ephedrine-containing plants are also 
exported from Osaka and Tokyo, Japan, and from Karachi and 
Rawalpindi, India. The world supply of these plants appears to have 


satisfied the demand during 1927, and is now greater, for the average 
price of Ma Huang shipped from Tientsin to the United States during 
1927 was U. S. $10.43 per 100 pounds, while during 1928 it fell to 

In contrast with the two concerns one German, one Japanese 
who were the sole purveyors of pure ephedrine prior to 1924, the drug 
is now being prepared by eight firms in the United States, by one in 
Canada, by three in England, by two in Germany, by three in China, 
by four Japanese companies, and by two in India. There may be 
others of which the writers are unaware. 

d. Physical and chemical characteristics. The alkaloid ephedrine 
is deposited from an ether solution as an oily substance, but colorless 
and odorless crystals appear as needles or rosettes on standing or 
recrystallization. These melt at 34-40C. and boil above 200C. 
The specific rotation, [a], of the base is between 6 and 7.5. 
The alkaloid is soluble in ether, chloroform, alcohol, petroleum 
ether, and water, the solutions being strongly alkaline to litmus 
paper. The crystallography of ephedrine has been investigated by 
Schwankte, and Walcott (quoted by Peterson, 1928). Geppert in- 
vestigated its effects upon the surface tension of water. A peculiar 
reaction of ephedrine is the formation of the hydrochloride when it is 
shaken with chloroform: this was pointed out by Peterson (1928), 
and is responsible for the high melting point incorrectly reported by 
Chen (1925) for ephedrine base. 

For laboratory and clinical uses the hydrochloride and sulphate 
derivatives are most commonly used. The hydrochloride appears as 
white odorless crystals, with a melting-point of 214-220, [a] 33 to 
35.5; it contains 17.3 to 17.7 per cent of C~, is soluble in water 
and alcohol, insoluble in chloroform, ether, and paraffine oil. The 
sulphate occurs as fine, white, odorless crystals, melting at 240-243C. 
[]" -29 to -30, containing 21.8 to 23.1 per cent of SCV -, soluble 
in water and hot alcohol, insoluble in ether, chloroform, and paraffine 

Solutions of ephedrine or its salts react with few of the alkaloidal 
reagents. With Mayer's reagent there is a turbidity or white pre- 
cipitate, according to the degree of concentration. Tsiang and Brown 
(1927) described characteristic micro-crystalline reactions when 


ephedrine is treated with Millon's reagent, gold chloride, platinic 
chloride, or Kraut's reagent. The most serviceable qualitative reac- 
tion of ephedrine is that with copper sulphate and sodium hydroxide, 
which was first pointed out by Nagai (1892) : a purple color appears, 
which is extractible with ether. This test is sensitive to one part of 
ephedrine in 400, and if the concentration exceeds 1 in 40 a pinkish 
purple precipitate is formed, and this is completely soluble in ether. 

The chemical behavior of ephedrine has been exhaustively studied 
by E. Schmidt, Nagai, E. R. Miller, Flaecher, Calliess, Emde, and 
others. Probably the most important property is its stability: 
ephedrine solutions are not decomposed by exposure to light, air, or 
heat, and age apparently does not affect their activity. Thus, a 
solution of ephedrine hydrochloride, prepared and sealed in a sterile 
ampule by the authors on December 23, 1923, showed no change in 
appearance when opened on March 14, 1929, and produced the custom- 
ary pressor response when injected into a pithed cat. Kendall and 
Witzmann (1927) have demonstrated the great resistance of ephedrine 
to oxidation, as compared with epinephrine: the former is not oxidized 
by dibromphenolindophenol, naphtholdichlorindophenol, methylene 
blue, or indigo carmine, while the latter is oxidized by all these agents. 

e. Structure and isomerism. The chemical constitution of ephedrine 
has been studied by Ladenburg and Oelschlagel, Nagai, E. Merck, 
E. Schmidt, E. R. Miller, Rabe, Ogata, and others. The empirical 
formula has been definitely established as C 10 Hi B ON, the structural 
formula as C^g-CHOH-CHCHs-NHCHs, or /3-phenyl-jS-hydroxy- 
a-methyl-ethyl-methyl amine, or l-phenyl-2-methylaminopropanol-l, 
or a-hydroxy-)9-methylamino-propyl benzene: 


Epinephrine Ephedrine 

Its chemical similarity to epinephrine is obvious. 
The above graphic formula of ephedrine contains two asymmetric 
carbon atoms, so that two sets of stereoisomers, making six in all, are 


possible. All have been prepared synthetically (see the following 
section); they are designated /-, d- } and dZ-ephedrines, d-, 1-, and 
<#-pseudoephedrines, the dl forms being optically inactive racemic 
mixtures. Only two occur in nature, namely /-ephedrine, which is 
the ephedrine now in use, and d-pseudoephedrine, which is also found 
in Ma Huang, and which is the pseudoephedrine first isolated by 
Merck from European Ephedra, and recently prepared by Chou and 
Read (1926) from Ma Huang extracts from which ephedrine had been 
removed. This is the pseudoephedrine of current literature. Pseudo- 
ephedrine is quite unlike ephedrine in melting-point (118C.), optical 
rotation ( [a]" + 50) and, to a certain extent, in physiological effects. 
It is of particular interest, however, because ephedrine can readily 
be converted into it under certain conditions, which were studied by 
E. Schmidt, Nagai, and Calliess, more recently by Chou (1926). 
The literature dealing with the isomerism of these alkaloids was 
reviewed by Chen and Kao (1926). Emde (1928) has obtained evi- 
dence that the OH and NHCH 8 groups are distant from each 
other in the ephedrine molecule but close together in the pseudo- 
ephedrine molecule. 

/. Other alkaloids occurring in Ma Huang. In addition to ephedrine 
and pseudoephedrine, three other related (but not isomeric) alkaloids 
have been isolated from Ma Huang. Smith (1927, 1928) obtained 
Z-methyl-ephedrine and nor-rf-pseudoephedrine. Nagai and Kanao 
(1928) confirmed these findings, and succeeded in isolating a third 
alkaloid, namely, ^-methyl-pseudoephedrine. It appears therefore, 
that ephedrine, like several useful alkaloids, occurs in nature along 
with closely related substances, though of these only pseudoephedrine 
occurs in appreciable quantity. 

g. Synthesis of ephedrine. E. Schmidt and his associates made 
various attempts and advances toward the synthesis of ephedrine. 
Fourneau (1904) prepared a compound having the formula of ephe- 
drine. He and his associates later succeeded in the synthesis by 
different methods. His process was patented in England (1927). 
Nagai accomplished the synthesis in 1911 and patented his product 
in Japan, the United States, Canada and England, under the name 
of Methylmydriatine. All these products were racemic, as is always 
the case when an optically active substance is synthesized. However, 


according to Ogata (1919), Nagai succeeded in 1918 in resolving his 
product into I- and ^-ephedrines. Recently, Nagai (1927) has stated 
that he was able to synthesize two racemic ephedrines, one melting 
at 40, the other at 70, and in separating each into its d- and /-com- 
ponents by means of tartaric acid: the pair obtained from the mixture 
melting at 70 he called isoephedrines (identical with pseudoephe- 
drines). Spath and Gohring (1920) described their complete success 
hi the synthesis and separation of all six isomers. Eberhard (1915) 
also succeeded in synthesizing racemic ephedrine. Kanao (1927) 
reported the success of his attempts to synthesize and separate the 
six isomers, confirming the results of and Gohring. E. Merck 
has recently placed synthetic racemic ephedrine on the market, under 
the name of Ephetonm; the process of preparation is patented in 
Germany and England. Manske and Johnson (1929) and Skita and 
Eleil (1929) have recently achieved new syntheses of ephedrine. 
Fourneau and Nicolitch, Manske and Johnson, and Neuberg, Jacob- 
son and Wagner employed chemical agents other than tartaric acid 
in the resolution of racemic ephedrine. 

It is obvious that the final confirmation of the deduced structure of 
ephedrine namely, synthesis of the substance has been furnished 
repeatedly. At present the natural product is more widely used than 
the synthetic and at the time of writing American manufacturers are 
supplying only natural ephedrine. 


Chen and Schmidt (1924) called the attention of the Western world 
to ephedrine in the belief that the actions of the drug were essentially 
sympathomimetic and that it should achieve a usefulness similar to 
that of epinephrine. This belief has been strengthened by subsequent 
clinical experience, and appears to be amply justified. However, 
when the actions of ephedrine are compared with the pattern of 
sympathomimetic effects i.e., the actions of epinephrine in the 
laboratory, differences are perhaps more frequent than analogies, and 
there has recently been a tendency on the part of several investigators 
to emphasize the differences as indicative of an absence of any sympa- 
thomimetic effect on the part of ephedrine. It is scarcely to be ex- 
pected, of course, that two different substances, however closely 


related, would possess physiological effects that are identical in all 
respects, but if it should be proved that the important actions of 
ephedrine are fundamentally different from those of epinephrine the 
present attitude of physicians toward ephedrine would have to be 
radically altered. On the whole, there appears to be no conclusive 
evidence that the actions of ephedrine that are of therapeutic impor- 
tance are not sympathomimetic, and there is considerable evidence 
that they are. On the other hand, there is scarcely any respect in 
which the effects of ephedrine are identical with those of epinephrine, 
and there are several instances in which the two substances have 
opposite actions upon the same structure or function. 

1. Action on lower forms of life 

Very little work has been done along these lines. Macht (1929), 
who has made a systematic study of the toxic effects of various sub- 
stances upon living plant organisms found that ephedrine was much 
less toxic than epinephrine to the seedlings of Lupinus Aldus, a con- 
centration of 1 in 5,000 of ephedrine having a phyto-toxic index of 
75 per cent. This is in accord with other observations of the same 
author, indicating that a drug of animal origin is more toxic to plants 
than one of vegetable origin. In the sea crab, Palaemon, kept in 
1 to 1000 solution of ephedrine, a temperature of 36 induces heat 
narcosis in 30 minutes (Frohlich and Kreidl, 1921). 

Nadler reported interesting results from experiments with the 
squid (Loligo pealii). He found that epinephrine and ephedrine, 
injected subcutaneously, produced local blanching, which was sup- 
posedly due to inhibition of smooth muscle of the chromatophore 
system. The effect of ephedrine differed from that of epinephrine in 
two respects, however. First, the blanching was much slower in its 
appearance when ephedrine was used, though it lasted 8 hours or more 
instead of 10 minutes, which was the duration of the epinephrine 
effect. Second, the animals injected with ephedrine showed a diffuse 
generalized reddish coloration excepting at the injected area; this 
coloration was also produced by intravascular or oral fl.rhrnniatrfl.tion 
of the drug. Since excitement or irritation of the animal likewise 
caused the same color change, it was ascribed to stimulation by 
ephedrine of the central nervous system of the animal; epinephrine 


apparently had no such effect. These results indicate that the action 
of ephedrine upon this animal is twofold: a peripheral epinephrine-like 
one, and a stimulant one on the central nervous system. 

Nadler also found that a number of substances produced peripheral 
effects opposite to those of epinephrine and ephedrine, namely, a local 
deep coloration at the site of injection. These were parathyroid and 
anterior pituitary extracts, posterior pituitary extract, and barium 
chloride. The last two are known to stimulate smooth muscle fibers 
directly, irrespective of their innervation (i.e., they are musculotropic), 
and the effects hi the squid were thought to be due to contraction of 
the chromatophore musculature. He found that epinephrine or 
ephedrine, injected in sufficient quantity into the red zone produced 
by injection of any of these agents, was able to antagonize the effect 
and produce local blanching. 

This is the only investigation, upon one of the lower forms of lit e, of 
the fundamental nature of the action of ephedrine. The conclusion 
was that the action of ephedrine is epinephrine-like (sympathomimetic) 
and not pituitrin-like (musculotropic). 

2. Actions on the circulation 

These are probably the most striking effects of ephedrine in the 
common laboratory animals, and it is somewhat strange that they 
were not investigated until comparatively recent times. If they had 
been, the present status of ephedrine might have been attained several 
decades ago. 

a. The effect upon blood pressure. The first work that of Miura 
(1887) led to the conclusion that ephedrine is essentially a circula- 
tory depressant. The doses used by him were excessive (fatal) 
ones, and cardiac depression evidently dominated the picture. Grahe 
(1895) reported a slight rise of blood pressure of curarized dogs upon 
subcutaneous or intravenous injection of ephedrine or pseudoephedrine, 
but his published tracings show barely detectable effects. He also 
found that subsequent injections led to a fall in pressure. The first 
demonstration of the characteristic pressor effect of ephedrine was that 
of Hirose (1915), who injected the drug intravenously in anesthetized 
rabbits. Amatsu and Kubota (1917) confirmed these results, and 
added the observation that the rise in pressure was not prevented by 


destruction of the medulla or by paralytic doses of chloral hydrate. 
Chen and Schmidt (1924) demonstrated similar effects in cats and 
dogs, and emphasized the relatively long duration of the effect of 
ephedrine, the diminution, disappearance, or reversal of the effect 
upon repeated injections, and the ability of ephedrine to raise blood 
pressure when taken by mouth. Since then many workers have con- 
tributed to the subject, and the principal features in the circulatory 
actions of ephedrine are well established. 

Ephedrine causes a rise in blood pressure of anesthetized dogs when 
injected intravenously in dosage of 0.005 to 30 mgm. per kilogram, 
but the greatest effect is produced by doses of 1 to 10 mgm. per kilo- 
gram: following such injection, blood pressure rises by 100 or more 
millimeters of mercury and is maintained at this level for at least IS 
to 25 minutes. In unanesthetized dogs, 5 to 10 mgm. of ephedrine 
per kilogram, by vein, was found by Pennetti (1928) to cause a rise in 
pressure lasting 3 to 4 hours. 

The pressor effect of ephedrine appears to be less marked in rabbits 
than in cats and dogs (Kreitmair, 1927). The minimum pressor dose, 
injected intravenously, was found to be 0.05 mgm. per kilogram in 
rabbits, while l/50th of this quantity was effective in cats. 

Large quantities of ephedrine (40 to 65 mgm. per kilogram) in- 
jected intravenously in dogs, cause only a fall in blood pressure 
(Chen and Meek, 1926) : these are close to the fatal dose. Kreitmair 
(1927) states that 10 mgm. or more per kilogram injected into a vein 
causes a fall in blood pressure in cats. This is the type of effect 
observed by Miura (1887), who apparently did not try smaller doses. 

When the pressor effect of ephedrine is compared with that of 
epinephrine, several outstanding points of difference are apparent. 
First, the effect of epinephrine is much more intense but much less 
prolonged than that of ephedrine: under optimal conditions, employ- 
ing intravenous injections in cats, the rise in pressure produced by 
epinephrine is 100 (Nagel, 1925) to 142 (Chen) times as intense as that 
of the same quantity of ephedrine, but the effect of ephedrine com- 
monly persists 7 to 10 times as long as that of epinephrine (Chen). 
Second, the intensity of effect of epinephrine is so closely proportional 
to the quantity injected that the pressor response can be employed 
in assaying epinephrine preparations (United States Pharmacopoeia, 


Ninth Revision); this is distinctly not the case with ephedrine, the 
circulatory effects of which are by no means proportional to the quan- 
tity injected (Chen and Schmidt, 1924) ; they may be less from large 
doses than from smaller ones. Third, following an intravenous injec- 
tion of epinephrine blood pressure frequently falls from the peak of the 
pressor effect to a subnormal level, rising slowly to normal; t.ln'g is not 
true of ephedrine, following which pressure simply falls very gradually 
to normal (Kreitmair, 1927). Fourth, when epinephrine injections 
are repeated the same degree of effect will be obtained from each; 
with ephedrine, however, the first dose is by far the most effective one, 
and upon repetition the pressor effect of each becomes progressively 
less until it disappears completely or is replaced by a depressor effect 
(Chen and Schmidt, 1924). This latter feature has been noted re- 
peatedly (Rowe, 1927; Rudolf and Graham, 1927; Kreitmair, 1927; 
Pittinger, 1928; Launoy and Nicolle, 1928) in cats, dogs, and rabbits, 
anesthetized or pithed. Its explanation involves factors which are 
also responsible for most, if not all, of the other differences between 
the circulatory effects of ephedrine and epinephrine, and the observa- 
tions bearing upon this question may properly be considered at this 

The extent to which the circulation becomes "tolerant" to repeated 
injections of ephedrine has been found to depend upon the size of the 
dose. Thus, comparatively large quantities (about 5 mgm. per kilo- 
gram), injected rapidly and at frequent intervals (5 to 10 minutes) 
very quickly become ineffective and soon lead to a depressor effect 
from each injection. On the other hand, small doses (0.02 to 0.05 
mgm. per kilogram) may show cumulative effects (i.e., a step-like 
rise in pressure to a sustained high level) if injected at close intervals 
(Chen, 1926), and if time is allowed for pressure to recover between 
injections each may sometimes though by no means always 
produce the same pressor effect. The explanation advanced (Chen 
and Schmidt, 1924) for the decreasing effectiveness of repeated injec- 
tions of ephedrine is that maximal pressor effects are soon developed, 
and that additional quantities of the drug are then incapable of 
producing further stimulant effects. It has been suggested (Chen and 
Meek, 1926) that the "receptors" with which ephedrine combines 
may be fewer in number, or more easily saturated, than those of 


epinephrine, which would account for the absence of progressive effects 
as the dose of ephedrine is increased above the optimum level. It 
seems probable that the greater persistence of ephedrine actions 
depends upon a more stable union with receptor substance than is the 
case with epinephrine and if the ephedrine receptors are saturated 
early the lack of progressive effect from repeated injections of ephe- 
drine is accounted for. When the quantities of ephedrine are small 
this saturation would not be accomplished until a number of injec- 
tions have been made. Such explanation appears to harmonize with 
experimental observations, and is the best available at present; it is, 
of course, purely hypothetical. 

The depressor effect of ephedrine was attributed by Chen and 
Schmidt (1924) to cardiac depression an effect which is well known 
and will be considered in the following section. It is wholly unlike 
the depressor action of epinephrine, which can be demonstrated with 
minm\al doses and is apparently due to stimulation of vasodilator 
nerve endings (Dale: Jburn. Physiol., 1906, xxxiv, 163): with ephe- 
drine, a first injection is always purely pressor unless it is very large; 
a depressor effect from a small or moderate dose can be demonstrated 
only after maximal pressor effects have been produced by previous 
injections, and there is no evidence that any dose of ephedrine can 
produce a vasodilator effect comparable with that of epinephrine. 
The fact that the pressor effect of epinephrine is often followed by a 
depressor (vasodilator) one, while that of ephedrine is simply followed 
by recovery to normal, also indicates that the ability to stimulate 
vasodilators is either lacking completely La ephedrine, or is very much 
less conspicuous than is the case with epinephrine. It may be noted 
also that the pressor action of ephedrine is more affected by the con- 
dition of the subject than is the case with epinephrine. Animals whose 
blood pressures have been lowered by trauma, operative procedures, 
hemorrhage, etc., show much less pressor effect than normals, and 
are more likely to show only a fall in pressure following a moderate 
dose of ephedrine (Chen, 1925). Deep anesthesia and consequent 
hypotension also increase the probability of fall in pressure after only 
a few injections of ephedrine (Chen, 1925) . Under such circumstances 
increasing the dose of ephedrine would be more likely to lead to fall 
than to rise hi blood pressure a contingency that is not encountered 
with epinephrine. 


In brief, it appears that the capacity of ephedrine to raise blood 
pressure is limited by two factors: first, by its relative weakness as 
a circulatory stimulant, perhaps because there are only relatively few 
"receptors" with which it can combine, and additional quantities of 
the drug are incapable of producing further effects once these have 
been saturated; second, by the depressant action of ephedrine upon 
the heart an effect that is masked by the pressor effect until the 
latter has become maximal, or unless overwhehning quantities are 
injected. Epinephrine is not subject to these limitations to anything 
like the same degree as ephedrine. This suggests that a mixture 
of the two drugs might possess the virtues of both the intensity of 
epinephrine and the persistence of ephedrine while TnimTnizing their 
respective disadvantages the evanescence of epinephrine and the 
danger of cardiac depression by ephedrine. This has actually been 
found to be the case. 

Thus, Chen and Meek (1926) found that upon intravenous injection 
of ephedrine and epinephrine in dogs there was summation, both in 
intensity and duration, of the pressor effect. Launoy and Nicolle 
(1928) report an actual potentiation when such injections are made 
in unanesthetized rabbits, the rise in pressure being greater than the 
sum of the effects of both drugs given separately. Cs6pai and Doles- 
shall (1928) found that ephedrine sensitizes the human circulation to 
intravenous injections of epinephrine, the influence being especially 
marked in cases of hyperthyroidism; they believe that ephedrine 
sensitizes sympathetic nerve endings just as thyroxin sensitizes the 
cells to the action of hormones. 

The action of ephedrine upon the human blood pressure has now 
been studied extensively, and with quite uniform results. The first 
study was that of Miller (1925), who reported rise in pressure in 70 
out of 84 individuals given a dose of 50 to 125 mgm. of ephedrine 
orally or by subcutaneous injection. In 7 cases pressure was not 
altered, while in 6 it fell. The rise in pressure varied from a few 
millimeters to 65, and its duration was 6 to 8 hours. Similar results 
were reported by Rowntree and Brown (1926), Pollak and Robitschak 
(1926), Rudolf and Graham (1927), Hess (1926), Jansen (1926), 
Kesten (1927), Middleton and Chen (1927), Althausen and Schu- 
macher (1927), Wu and Read (1927), Cs6pai and Fernbach (1928), 


Radoslav and Stoicesco (1927), and Pennetti (1928). Anderson and 
Homan (1927) observed a rise in pressure in children given 15 mgm. 
of ephedrine hydrochloride. The results of Rowntree and Brown 
(1926), and of Hess (1926), indicate that blood pressure can be main- 
tained at an elevated level for several days by means of daily ad- 
ministration of ephedrine. All observers agree that ephedrine is 
effectively absorbed following oral administration, and Hess (1926) 
has shown that rise in blood pressure also occurs following rectal ad- 
ministration of ephedrine, in dosage of 2 mgm. per kilogram, as 
suppository, hi miTTr or dissolved in the proctoclysis fluid. Intra- 
venous injection was first tried by Miller (1925), subsequently by 
Jansen (1926). The effects are more marked than those of other 
routes of administration, but last only 15 to 30 minutes (Jansen). 

The influence of disease upon the pressor effect of ephedrine in 
man has been studied by several workers. In Graves' disease, in 
which there is conspicuous sensitization to epinephrine, Pollak and 
Robitschek (1926) reported unusually marked pressor effects from 
ephedrine, but Cs6pai and Fernbach (1928) concluded that there is no 
sensitization to ephedrine in Graves 5 disease. In asthma, Thomas 
(1926) and MacDermot (1926) found no rise in pressure following 
oral administration of ephedrine, and a similar statement was made 
in an earlier review by Chen and Schmidt (1926). However, studies 
of larger series of cases by Althausen and Schumacher (1927) andMid- 
dleton and Chen (1927) have shown that ephedrine raises blood pres- 
sure in asthmatic patients, possibly less frequently than in normals, 
but to as high a level and for as long a time. Pennetti (1928) tried 
ephedrine in a single case of myxedema and found a fall in blood pressure 
from 210 to 145 mm. of mercury. 

The effect of repeated doses of ephedrine, taken by mouth, upon the 
blood pressure of human beings has been investigated by Rowntree 
and Brown (1926) and by Chen (1928). It appears that when a 
therapeutic dose (50 mgm.) is taken by mouth every two to three 
hours the first causes the most marked rise in pressure, the subsequent 
ones causing further but smaller rises in the already elevated pressure 
and mamtaining it at an abnormally high level as long as the drug is 
given regularly. These results are therefore similar to those obtained 
by intravenous injections of small doses (0.02 to 0.05 mgm. per 


kilogram) at short intervals in anesthetized dogs, and appear to indi- 
cate that the pressor effect of such dosage is not nearly maximal. 
The circulatory effect of a single dose of ephedrine, taken by mouth, 
evidently disappears completely within 14 to 24 hours, a second dose 
of the same size then producing practically the same effect as the first 
(Chen, 1928). 

The effect of ephedrine upon venous pressure was studied by Chen 
and Meek (1926) in two dogs, one of which was atropinized. In 
each, a slight fall in venous pressure coincided with the rise in arterial 

b. The action on the heart. The first investigations of the physio- 
logical effects of ephedrine disclosed its power of depressing the heart. 
Miura (1887) observed that lethal doses of ephedrine caused diastolic 
arrest of the frog's heart. Grahe (1895) found that ephedrine or 
pseudoephedrine, applied to the frog's heart by irrigation or injected 
intravenously, caused depression and irregularities, and that a heart 
arrested by either drug could not be made to beat by means of atro- 
pine, though a heart arrested by muscarine could be made to beat when 
treated with ephedrine or pseudoephedrine. Amatsu and Kubota 
(1917) obtained similar results with frog's heart studied by Engelman's 
and Straub's methods, confirming the inability of atropine (as well as 
camphor) to overcome the depressant effect of ephedrine. Chen 
and Schmidt (1924) found only depression of the frog's heart irrigated 
with ephedrine. 

Subsequent investigations have confirmed the conclusion that 
ephedrine is essentially depressant to the frog's heart, while showing 
in addition that small quantities may exert an inconspicuous stimulant 
effect. Chen and Meek (1926) found that ephedrine sulphate, 
applied to the heart in concentration of 1 in 1,000, may cause accelera- 
tion by a few beats per minute, but a 1 in 100 solution was purely 
depressant to rate and amplitude. Barlow and Sollmann (1926), 
who perfused the heart by the method of Howell and Cooke, found 
pure depression with concentrations of ephedrine sulphate of 1 in 
10 B or stronger, rate, force and output being Himim'shed, and with 
1 in 10 s dilutions complete heartblock was elicited; stimulation was 
occasionally observed with dilutions of the order of 1 in 10 7 , being 
manifested as an increase in rate and amplitude, but the increase 


rarely exceeded 10 per cent. Kreitmair (1927) noted increase in 
amplitude of the frog's heart perfused by Straub's method with 1 in 
10 4 ephedrine hydrochloride; rate was not affected, and higher con- 
centrations were purely depressant, 1 in 100 causing arrest that could 
be combated by means of perfusion with 1 in 10 4 dilution of epineph- 
rine, with calcium, or with histamine, but was not reversible upon 
simple perfusion with pure Ringer's solution, and was not affected by 
atropine. Gradinesco (1927) also found that epinephrine is able to 
restore the beat to the frog's heart arrested by perfusion with ephe- 
drine. Gomes da Costa (1927) reported stimulant effects of dilute 
solutions of ephedrine upon the perfused frog's heart, but LeVy and 
Boyer (1927) found only depression when any effect was evident. 
M6hes and Kokas (1929) likewise observed depression of the frog's 
heart perfused with a 1 in 50,000 dilution of ephedrine, and believed 
that the effect was partly removed by small quantities of atropine. 

The hearts of certain invertebrates have also been studied with 
respect to the effects of ephedrine. L6vy and Boyer (1927) studied 
the heart of the snail (Helix pomatia) and found systolic contracture 
with a 1 in 20 solution of ephedrine; weaker solutions (1 in 100, 1 in 
1,000) caused a slowing in rate and an increase in strength of con- 
traction, with periodic variations. Bain (1929) perfused the hearts 
of crabs (Maia squinado, Cancer pogurus, and Carcinus moenas) 
with ephedrine, among other drugs, including epinephrine which, in 
1 to 50,000 dilution caused a marked increase in rate and tone of the 
hearts: ephedrine was used in the same dilution as epinephrine, and 
produced no effect whatever. Apparently a stronger solution of 
ephedrine was not used, so that one can conclude only that ephedrine 
is weaker than epinephrine in its effects upon these hearts, as upon all 

The isolated heart of the toad was perfused with ephedrine and 
pseudoephedrine by Loo and Read (1928) : they usually found depres- 
sion of amplitude of beats with 1 in 20,000 ephedrine following 
pseudoephedrine but ocasionally ephedrine caused acceleration. 

The turtle's heart was perfused with ephedrine by Chen and Meek 
(1926): dilutions of 1 in 10,000 sometimes accelerated the rate 
slightly, but 1 in 1,000 or 1 in 100 caused bradycardia, usually with 
decrease in amplitude, culminating in diastolic arrest. 

The action of -tlie wt|ip^to*te^ -was investigated 
by Chen and Schmidt (1924) as4 fey C^JMMeek (1926), Pulse 
rate in the intact unanesthetigeci 4o^fe?^&aly flowed, occasionally 
accelerated, when qpbedvm Is^^ete^.-^ojKMtaniecaisly or intra- 
venously; in the wfti^^i anfml acetottfco* is cesissjenly ob- 
served following i&tmv&Qi3s InjeetMHx of -less *ha&,i s&g&t* $e* laio- 
gram, though a&ej^aarg^.goses (1 tJ$ mgD^ perfefioam j$$} 
commonly seeav Atropbs c$pjgiafed^,$lx>Kshes or 
bradycardiay which is tbl^to bfc ix^rd4^ a reflex eSect of 
in blood pressure, the stewing being greater is splmalfa whose 
mhibitory centers are not depressed by anesthesia* This explanation 
is, however, called into question by the recent experiinents of Pene&etti 
(1928), who found that section of the vagi or injection of atropine in 
unanesthetized dogs does not usually accelerate the heart slowed by 
ephedrine. Confirmation of these results is highly desirable. Coelho 
(1929) reports that in dogs narcotized with chloralose, ephedrine, hi 
dosage of 1 to 20 mgm. per kilogram, causes acceleration of the heart. 

The strength of the beats of mfl-mTnalian hearts has also been found 
to be increased by ephedrine. Chen and Schmidt (1924) recorded the 
contractions of part of the right ventricle (myocardiograph) and found 
them markedly increased by ephedrine. The effect was not pre- 
vented by section of the vagus nerves or by atropine, was not due to an 
atropine-like effect upon cardio-inhibitory nerves, and was fully 
comparable with that of electrical stimulation of the accelerator nerve 
or of injection of epinephrine. They also showed that ephedrine 
caused increase in rate and amplitude of ventricular contractions 
when applied locally to the stellate ganglia a feature in action that is 
not shared by epinephrine (Chen and Meek, 1926). Intravenous 
injection of ephedrine caused still further acceleration and augmenta- 
tion. Large quantities of ephedrine (40 to 55 mgm. per kilogram by 
vein) are apt to cause acute cardiac depression (Chen and Meek, 1926). 
The cardiac stimulant action of small quantities of ephedrine and the 
depressant action of large quantities have also been observed by 
Kreitmair (1927) on cats and by Launoy and NicoUe (1928) on rabbits. 
Chopra, Dikshit, and Pillai (1929) found increase in auricular con- 
tractions in cats given 2 mgm. injections, the ventricles being un- 
affected, while with 5 mgm. both auricles and ventricles were 


It has been shown by La Barre (1928) that ephedrine does not lead 
to ventricular fibrillation in cats under chloroform anesthesia; in 
this respect ephedrine differs from epinephrine. 

Studies of the effect of ephedrine upon the cardiac output of 
dogs were made by Chen and Meek (1926) by means of cardiometric 
and teleoroentgenographic methods. They concluded that in the 
(anesthetized, atropinized) dog there is a distinct and constant in- 
crease in volume output per minute at the time of increase in pulse 
rate and rise in blood pressure. Wilson, Pilcher, and Harrison (1928) 
employed the Fick principle to measure cardiac output of unanesthe- 
tized dogs, and found that ephedrine caused an increase in minute 
volume, especially when the drug was given subcutaneously or by 
mouth. Halsey, Reynolds, and Blackberg (1927) employed the same 
methods but obtained opposite results, i.e., ephedrine was found to 
decrease the cardiac output of unanesthetized dogs as well as of dogs 
narcotized with chloroform or chloral hydrate. It should be noted 
that results obtained by this procedure are frequently opposed to 
those obtained by other methods. For example, digitalis, which has 
been universally regarded as a stimulant to cardiac muscle and is 
found to be such by other methods of investigation, decreases cardiac 
output as measured by the Fick method and appears to be essentially 
a cardiac sedative (Harrison and Leonard: Jour. Clin. Invest., 1926, 
iii, 1) ; and quinidine and chloral hydrate, which, by other methods of 
investigation, are shown to be marked cardiac depressants, appear 
as cardiac stimulants according to the results obtained by this method 
(Halsey, Reynolds, and Blackberg, 1927). Until such discrepancies 
are satisfactorily explained it is impossible to evaluate the results 
obtained with respect to ephedrine. 

Electrocardiographs studies made by Chen and Meek (1926) 
in unanesthetized and anesthetized animals, showed that small doses 
(5 to 10 mgm. per kilogram by vein in dogs) did not alter the contour 
of the curve, apart from the T-wave, which might be flattened, in- 
verted, or occasionally augmented. Massive doses (40 to 75 mgm. 
per kilogram), given intravenously to dogs and rabbits, appeared to 
depress the automatic and conducting systems in descending order, 
that is, from sino-auricular node to the ventricular terminations of the 
Purkinje system: there were, in the order of their appearance, brady- 


cardia, prolongation of the P-R interval, partial auriculo-ventricular 
block, nodal rhythm, ventricular automatism or extrasystoles, bundle 
branch block, finally ventricular fibrillation. Similar results were 
obtained by Coelho (1928) in dogs narcotized with chloralose. 

The isolated mammalian heart has also been studied: Chen and 
Schmidt (1924) and Chen and Meek (1926) found that the rabbit's 
heart perfused according to LangendorfF's method was stimulated in 
rate and strength of beats by low concentrations (1 in 100,000) of 
ephedrine sulphate, while stronger solutions (1 in 10,000, 1 in 5,000) 
caused depression of both rate and strength; still stronger solutions 
(1 in 2,000) brought about partial block, and 1 in 1,000 caused prompt 
failure (Chen and Meek, 1926). Similar results were obtained by 
Chopra, Dikshit, and Filial (1929), and by Pennetti (1928); the latter 
found that epinephrine was able to revive a heart arrested by 

The effects of ephedrine upon the human heart have received con- 
siderable study. The effect upon pulse rate was observed by Chen and 
Schmidt (1924) in a small series of cases, all of whom showed a slowing 
after oral or subcutaneous administration of ephedrine. Miller 
(1925), in a much larger series, found slowing of the pulse duiring the 
rise in blood pressure in the majority, but in 16 of his 84 subjects 
pulse rate was accelerated by ephedrine. Pulse rate and blood 
pressure returned to normal at about the same time. Rowntree and 
Brown (1926) noted acceleration of the pulse as frequently as slowing, 
and Middleton and Chen (1927) observed that acceleration was pro- 
duced more frequently than slowing. In the experience of Hess 
(1926) and of Rudolf and Graham (1927), a decrease in pulse rate was 
the more frequ'ent result of ephedrine, but in the cases of Jensen 
(1926) acceleration was the more frequent. In some cases in all these 
series pulse rate was unaffected. On the whole, the effect of ephedrine 
upon the rate of the human heart appears to be of the same nature as 
that upon the dog's heart, namely, acceleration or slowing, depending 
upon conditions which are not well understood. The influence of 
atropine upon the cardiac effects of ephedrine in man has apparently 
not been investigated, but it may be inferred that bradycardia follow- 
ing a therapeutic dose of ephedrine is a reflex effect of the rise in blood 


Evidence that ephedrine increases the strength of contractions of 
the human heart was obtained by Miller (and Pendergrass) (1925) 
by means of fluoroscopic observations of three individuals, in every 
one of whom the excursion of the ventricular and aortic shadows was 
greater after ephedrine than before. At the same time the apex 
impulse became visibly and palpably more forceful and the heart 
sounds became louder. These observations furnish an explanation of 
the palpitation which is commonly complained of by patients receiving 
ephedrine. Miller (1925) has also called attention to the occasional 
appearance of systolic murmurs in patients who had normal sounds 
before ephedrine was given, and to the intensification of existing 
systolic murmurs by ephedrine. These murmurs may be heard at the 
apex alone, at the base alone (in either aortic or pulmonary area), 
or in all these areas. He suggested that they might be the result of 
distention of the cardiac chambers leading to the relative stenosis of 
aortic or pulmonary orifices, or to relative insufficiency of the mitral 

Electrocardiographic studies of the effects of ephedrine in man were 
made by Middleton and Chen (1927) in 11 patients, the drug being 
taken by mouth; seven showed no change, four developed ventricular 
or auricular extrasystoles, these being most marked in a patient with 
chronic myocarditis in whom systolic blood pressure fell 30 mm. 
following ephedrine. Pennetti (1928) studied the electrocardiograms 
of 8 subjects with normal cardiovascular systems upon subcutaneous 
injection of 50 mgm. of ephedrine. Five of these showed perfectly 
normal tracings after the drug was- given, while in three there was some 
change decrease or increase in height of the R wave and prolonga- 
tion of the S wave, and in one the T wave became diphasic. 

The observations bearing upon the action of ephedrine upon the 
heart may be summarized as follows : there is no doubt that ephedrine, 
in large dosage, is depressant to the amphibian or mammalian heart, 
and may cause acute cardiac failure. This action is apparently exerted 
directly upon the muscular and neuromuscular tissues of the heart, 
and is independent of effects upon the cardiac nervous mechanism. 
The cardiac stimulant effect of smaller quantities of ephedrine is like- 
wise well marked in the case of the mammalian and human heart, less 
so in the amphibian heart. This effect is fully comparable with that 


of excitation of the accelerator nervous mechanism of the heart, 'by. 
means of electrical stimuli or epinephrine. The effect of ephedrine 
differs from that of epinephrine in that it is apparently exerted not 
only upon the extreme peripheral parts of the accelerator system, but 
upon its ganglia as well. 1 In the cardiac effects of ephedrine one sees 
the same general differences from epinephrine that are evident in the 
effects upon blood pressure: ephedrine effects are less intense but much 
more prolonged, and upon increasing or repeating the dose of ephe- 
drine the stimulant effect is increased little or not at all, or may be 
replaced by a depressant effect. The ability of ephedrine to increase 
the rate and force of heart beats is limited not only by an apparently 
small number of receptors, but also by its capacity for depressing heart 
muscle. Its cardiac stimulant effect cannot be made as intense as 
that of epinephrine by increasing the dosage and this fact, together 
with the deleterious effects of large doses upon heart muscle, make the 
intravenous or intracardiac administration of ephedrine inadvisable 
when stimulation is needed in an emergency. 

c. The action on blood vessels. Ephedrine produces vasoconstriction. 
This was first demonstrated in 1917 by Amatsu and Kubota by means 
of perfusion experiments. They observed constriction of vessels of 
frogs' legs upon perfusion with a concentration of 1 in 10,000 of 
ephedrine hydrochloride; the vessels of the ear of the rabbit were 
constricted by solutions ranging from 1 in 2,000 to 1 in 20,000; con- 
striction was also noted in the perfused vessels of the intestine, 
spleen, and kidney of the dog. Their results have been connrmed by 
perfusion experiments made by Chen and Schmidt (1924) on the dog's 
kidney, by Chen and Meek (1926) on the kidney, spleen, and leg of 
the dog, by Barlow and Solhnann (1926) and by MShes and Kokas 
(1929) on the frog, by Loo and Read (1928) on the toad, the latter 
finding a 1 in 20,000 solution effective. Other workers, while agreeing 
that ephedrine is a vasoconstrictor, found it a much less powerful one 
than these results would indicate. Thus, Kreitmair (1927) found 

1 This has been recently denied by Tainter (1929) who found that ephedrine, applied 
to the stellate ganglion, caused cardiac acceleration only exceptionally, and that similar 
effects could be produced by application to the pleura itself. He calls attention to the 
acidity of ephedrine solutions as a probable factor in the result obtained by Chen and 
Schmidt (1924). 

2988 G I 


constriction of frog's vessels with a 1 in 10 dilution of ephedrine, 
but none with a 1 in 100 solution; Gradinesco (1927) found only slight 
constriction with a 1 in 100 solution, and Schaumann (1928) obtained 
only slight constriction with concentrations less than 1 in 1,000. 
The last-named investigator found that a very small amount of epi- 
nephrine augmented the constrictor action of ephedrine, and that re- 
peated applications or an increase in concentration of ephedrine were 
less effective, ineffective, or might cause dilatation of vessels. 

Plethysmographic investigations have also disclosed the ability of 
ephedrine to constrict blood vessels, and have furnished additional 
information concerning its relative effectiveness upon different parts 
of the vascular system. Chen and Schmidt (1924) reported that 
intravenous injection of ephedrine in dogs caused immediate decrease 
in volume of the kidney only, and this decrease was followed by in- 
crease to a level far above normal. Increase in volume as blood pres- 
sure rose was usually observed in the intestines and invariably in the 
leg. Chen and Meek (1926) obtained similar results; they also re- 
corded volume of the spleen and found it usually decreased during the 
rise in blood pressure produced by ephedrine. Rudolf and Graham 
(1927) noted that the volumes of intestines and leg of the dog were 
slightly increased at first, but subsequently decreased, indicating 
delayed vasoconstriction. Gradinesco and Marcu (1927) reported 
increase in splenic volume; kidney volume was increased following 
small doses, but with large ones it was first decreased, then increased. 
Lim, Necheles and Ni (1927), who recorded the volume of the vivi- 
perfused stomach of the dog, obtained evidence of vasoconstriction by 
ephedrine, but a slight increase in volume was sometimes noted. 

These results leave no doubt concerning the ability of ephedrine to 
constrict certain blood vessels, nor concerning its status as a vaso- 
constrictor that is much less powerful and uniform in its effects than 
epinephrine. Yet it appears that the vasoconstrictor action of ephe- 
drine, like that of epinephrine, is essentially peripheral, and is not 
dependent upon stimulation of the vasomotor center or other parts 
of the central nervous system. This was shown by Amatsu and Ku- 
bota (1917), and by Chen and Schmidt (1924), who found ephedrine 
effective hi raising the blood pressure of animals whose central nerv- 
ous systems were destroyed or paralyzed. The same conclusion was 


reached by Marcu and Gheorghiu (1927) as a result of observation of 
simultaneous changes in carotid and crural blood pressures, and by 
Heymans (1928), who employed crossed-circulation experiments to 
exclude the central nervous system; the former found that ephedrine 
still raised blood pressure after exclusion of cardiac and splanchnic 
effects. But since plethysmographic experiments have shown that 
vasoconstriction is evident only in certain organs (kidney, spleen) 
as blood pressure rises following ephedrine it is clear that the effect is 
not exerted in the same degree upon all blood vessels a conclusion 
that is equally applicable to epinephrine. 

Concerning the part of the vascular bed that is affected by ephe- 
drine, little information is available. Kreitmair (1927) reported that 
a 1 per cent solution of ephedrine, locally applied to the web or tongue 
of a frog, causes constriction of arterioles and obliteration of capil- 
laries. Chen (unpublished) studied the circulation of the frog's 
tongue, web, mesentery, and kidney, but was unable to detect any 
significant changes upon local application or intravenous injection of 
ephedrine until a sufficient quantity had been given to depress the 
heart, when the observed effects could be attributed wholly to cardiac 
depression. H. C. Hou (personal communication) obtained practi- 
cally the same result. It appears, therefore, that ephedrine has not 
the intense constrictor action upon the extremely peripheral parts 
of the vascular bed that is so conspicuous a feature in the case of 
epinephrine. This may explain to a considerable degree the greater 
readiness with which ephedrine is absorbed into the circulation; it 
also makes ephedrine unsuitable for combination with local anesthetic 

The action of ephedrine upon blood vessels that are not markedly 
constricted by epinephrine (coronary, pulmonary, cerebral) has not 
been studied systematically. Chen and Schmidt (1924) found that 
ephedrine, like epinephrine, increased the outflow from the coronary 
vessels of the rabbit's heart perfused by Langendorff's method. 
Schmidt (1928) reported increase in venous outflow from the brains 
of dogs and cats given pressor doses of ephedrine, as well as epineph- 
rine, but pituitrin had the same sort of effect. The effects upon the 
pulmonary circulation apparently have not been studied. 

Some information has been obtained concerning the action of 


ephedrine upon human blood vessels. Marcu (1926) applied a ple- 
thysmograph to one arm and a cuff for sphygmomanometry to the 
other. He concluded that minimal doses of ephedrine (less than 1 
mgm. by vein) caused dilatation followed by constriction of abdominal 
vessels, while small doses (less than 10 mgm.) caused generalized con- 
striction in splanchnic and other vessels; larger doses had the same 
general effect, but constriction of abdominal vessels became relatively 
more marked. Apparently the splanchnic circulation of man is most 
susceptible and is most powerfully affected by ephedrine, and this is in 
harmony with the results of plethysmographic experiments in ani- 
mals. Rowntree and Brown (1926) studied the effects of intradermal 
injection of 10 per cent ephedrine in saline solution. The reaction 
was a small red central area surrounded by a patchy white border of 
irregular outline and inconstant appearance; reflex erythema was 
frequent. Epinephrine, similaly injected, caused a small white cen- 
tral area, surrounded by a zone of erythema. This confirms the 
results obtained by observation of the effects of ephedrine on capil- 
laries of the frog in indicating that ephedrine has little or no con- 
strictor effect upon capillaries. The ability of ephedrine to constrict 
the vessels of the nasal mucous membrane of man when the drug is 
taken by mouth has been proved repeatedly and will be considered in 
the section dealing with clinical uses. 

3. The action on respiration 

Apart from its effect upon the respiratory passages, which are due 
wholly to peripheral actions, ephedrine is a stimulant to the respira- 
tory center, resembling caffeine in its effects. In intact am'-mals small 
doses of ephedrine (5 mgm. per kilogram subcutaneously, 1 mgm. per 
kilogram by vein) have no significant effect upon respiratory rate or 
depth, and the same is true of human beings given therapeutic doses 
(Jansen 1926). In anesthetized animals the results appear to be 
somewhat variable hi detail but stimulation is a common result. 
Fujii (1925) found that the respiration of urethanized rabbits was 
increased in rate and decreased in depth by ephedrine hi dosage of 
10 mgm. per kilogram. Kreitmair (1927), using cats anesthetized 
with urethane and ether, found that 5 mgm. of ephedrine per kilo- 
gram caused increase in depth of respiration, rate being unaffected. 


Suzuki (1928) gave larger doses (30 mgm. per kilogram) to rabbits 
and noted as a rule an increase in depth with decreased rate of breath- 
ing, though occasionally rate was increased markedly. Schmidt 
(1929) found that ephedrine was more regularly effective than any 
of the conventional respiratory stimulants in combating extreme 
respiratory depression due to morphine. Toxic or lethal doses of 
ephedrine always produce acceleration of respiratory rate immediately 
before final failure of breathing, in intact or anesthetized animals 
(Miura, 1887; Chen, 1926; Kreitmair, 1927); this may be due to a 
large extent to acute circulatory depression. 

The action of ephedrine upon the respiratory center seems to con- 
sist of two distinct components: first, an increase in blood supply of 
the center, due to the pressor effect; second, a direct stimulant action 
upon the cells of the center. The result of ephedrine action is there- 
fore equivalent to that of a combination of epinephrine and caffeine. 
Ephedrine appears to be the most useful single respiratory stimulant 
that is available at present (Schmidt, 1929) . 

4. The action on smooth muscle 

In the effects that have been considered up to this point ephedrine 
differs only quantitatively from epinephrine. When the actions of the 
two agents are compared upon smooth muscle in general however, 
it is soon evident that the effects of ephedrine are sometimes opposite 
to those of epinephrine. Since the latter are due, in so far as is known 
at present, wholly to stimulation of the sympathetic ionervation of the 
muscle, it is clear that ephedrine either lacks this power or else applies 
it to the various parts of the sympathetic system with relative intensi- 
ties that are different from those of epinephrine. 

a. Pupil. Ephedrine produces mydriasis when applied locally to 
the conjunctiva or when absorbed into the circulation. This was first 
demonstrated by Miura (1887) and by Takahaski and Miura (1889) 
in dogs, cats, and rabbits, as well as humans; the pupils of chickens 
and pigeons were not dilated by ephedrine. These earliest workers 
left little to be added to the analysis of this feature in the action of 
ephedrine. They found that the light and accommodation reflexes 
were not abolished by the drug; that electrical stimulation of the oculo- 
motor nerve caused contraction of the pupil dilated by ephedrine; 


that section of the cervical sympathetic nerve or extirpation of the 
superior cervical ganglion did not prevent ephedrine mydriasis; 
that the latter could be diminished or overcome by means of muscarine, 
pilocarpine, or physostigrm'ne, as well as nicotine; that atropine did not 
cause further mydriasis after ephedrine had produced its complete 
effect. They concluded (1889) that ephedrine mydriasis is due to 
stimulation of the sympathetic pupillo-dilator mechanism and does 
not involve paralysis of the parasympathetic (oculomotor) pupillo- 
constrictors. The results have been confirmed in all respects by Grahe 
(1895), by Hirose (1915) and Miura (1912) on enucleated eyes of frogs, 
by Chen and Schmidt (1924) on the eyes of dogs, cats, rabbits and men, 
by Koppinyi (1928) on the eyes of guinea-pigs, and by Poos (1927) 
on the isolated sphincter and dilator muscles of the eyes of rabbits 
and calves. The latter was able to show that ephedrine like epineph- 
rine and cocaine causes increase in tone of the dilator muscle, 
decrease in that of the sphincter; the stimulant effect upon the dilator 
was augmented by increasing the alkalinity of the solution. This 
may explain the result obtained by Munch (1928), confirmed by Swan- 
son, Thompson and Rose (1929), that ephedrine base is a more power- 
ful mydriatic in the cat than is the alkaloidal sulphate or hydro- 

Chen and Schmidt (1924) confirmed the results of Miura, adding the 
observation that ephedrine does not cause loosening of corneal epi- 
thelium. Kreitmair (1927) stated that while ephedrine injected 
intravenously is about equally effective in causing mydriasis in dogs, 
cats, and rabbits, local application to the conjunctiva causes much less 
mydriasis in cats than in the other animals. 

Comparing the pupillary effects of ephedrine with those of epineph- 
rine, an essential difference is at once evident in the fact that while 
epinephrine has little or no effect upon the normal pupil, whether the 
drug is applied locally or injected intravenously, ephedrine is a highly 
effective dilator of the normal pupil, by any mode of administration. 
Schmidt (unpublished results) recently compared the effects of the two 
drugs upon the pupils of three rabbits each of whom had had the left 
superior cervical sympathetic ganglion removed several months pre- 
viously: epinephrine, locally applied to both eyes or injected intra- 
venously, dilated only the pupil of the operated side, while ephedrine, 


similarly exhibited, dilated both pupils, but the normal one more 
markedly than the other; pituitrin, locally applied, did not dilate either 
pupil. In these animals, as well as in the ones previously used by Chen 
and Schmidt (1924), cocaine dilated only the normal pupil. It is 
obvious that denervation does not sensitize the pupil to the effect of 
ephedrine as it has long been known to do to that of epinephrine. On 
the other hand, the structures upon which ephedrine acts to produce 
mydriasis do not degenerate after excision of the superior cervical 
ganglion, as appears to be the case with those upon which cocaine acts. 
Yet the action of all three drugs is essentially peripheral, as shown not 
only by the fact that the effect is limited to the eye to which they are 
applied, but also by the results obtained with the excised surviving 
muscle (Poos, 1927). The sensitization of the denervated pupil to 
epinephrine was attributed by Meltzer and Auer (1904) to the re- 
moval of inhibitory influences exerted by the ganglion upon the peri- 
pheral receptors with which epinephrine reacts, assuming that the 
latter do not degenerate under such conditions. On this basis, it 
would be necessary to conclude that cocaine acts upon receptors all of 
which degenerate following removal of the ganglion, and that ephe- 
drine, the effects of which are weakened but not abolished by such 
removal, acts partly upon cocaine-like receptors and partly upon 
epinephrine-like ones. 

b. Gastro-intestmal tract. In contrast with the effects of epineph- 
rine, which are uniformly like those of stimulation of the sympathetic 
innervation of this system, the effects of ephedrine appear to be 
irregular and uncertain. 

The effects upon the oesophagus were studied by To (1921), using 
the isolated organ of the frog. He found that ephedrine relaxed its 
tone in concentration of 1 in 2,000, and exerted a potentiating effect 
when given together with atropine or papaverine. 

The crop muscles of the pigeon were found by Hanzlik and Butt 
(1928) to be thrown into contraction by ephedrine in dosage of 10 to 20 
mgm. per kilogram; the effect involved both circular and longitudinal 
musculature, lasted 5 to 10 minutes, and was not prevented by atro- 
pine, though it was reduced by cocaine. 

The effects of ephedrine upon the stomach in situ were studied in 
unanesthetized dogs with permanent fistulae by Kinnaman and Plant 


(1927); they gave 5 mgm. of ephedrine per kilogram by vein, and 
found prompt and marked relaxation of gastric tone with inhibition 
of gastric motility, lasting 4 to 5 hours. Schmidt (unpublished) 
recently had the opportunity of repeating this experiment upon a 
single dog; following subtutaneous injection of 1 mgm. of ephedrine 
per kilogram, there was relaxation of tone and inhibition of gastric 
peristalsis for about 2 hours. In none of these experiments was there 
any trace of a stimulant action by ephedrine upon the gastric muscle 
of the unanesthetized dog, and inhibition (the epinephrine-like effect) 
was uniformly observed. M'Crea and Macdonald (1928) found that 
ephedrine, like epinephrine, inhibited gastric peristalsis and caused 
fall in intragastric pressure of anesthetized cats. The effects of 
ephedrine upon the human stomach have also been investigated. 
Pollak and Robitschek (1926) made roentgenologic studies: they 
observed an increase in gastric peristalsis, leading to expulsion of the 
barium meal into the duodenum, J to 1 minute after the subject had 
swallowed 20 drops of 10 per cent solution of ephedrine. They state 
that epinephrine caused a similar effect, which, they believe, may have 
been due to direct excitation of the musculature or to reflex stimula- 
tion consequent upon irritation of the mucous membrane. Marcu and 
Savuiesco (1928) recorded gastric motility by means of a balloon which 
was swallowed and connected to a water manometer; upon intrave- 
nous injection of 1 cc. of a 1 in 500,000 solution (0.002 mgm.) of ephe- 
drine they observed transitory contraction of the stomach, 0.02 to 
0.05 mgm. had no effect, while 0.1 mgm. caused inhibition of contrac- 
tions for about 10 minutes; upon intravenous injection of 20 mgm. of 
ephedrine, there was marked and prolonged inhibition of gastric move- 
ments, with a stimulant after-effect. 

The effects upon the small intestine in situ have received less atten- 
tion. Using unanesthetized dogs with fistulae of the ileum, Kinnaman 
and Plant (1927) found that ephedrine, injected intravenously, uni- 
formly caused immediate relaxation and inhibition of motility, fol- 
lowed by a stimulant effect that became more marked as the dose was 
increased. With 0.5 to 1 mgm. per kilogram inhibition was marked, 
lasted 30 minutes to 2 hours, and was followed by only slight stimu- 
lation, but with 5 mgm. per kilogram the period of inhibition was 
shorter and the stimulant after-effect was more marked. Schmidt 


(unpublished experiments) tried the effect of intramuscular injections 
of 2 mgm. of ephedrine per kilogram in four unanesthetized dogs with 
fistulae of the ileum, making 13 observations in all. In eight, there 
was pure decrease in motility, ranging from slight to marked; in two 
there was no distinct effect; in two there was brief inhibition followed 
by increase in motility; in only one case was there pure stimulation 
after ephedrine, and this was insignificant compared with the effect 
of local application of an aromatic water or intramuscular injection of 
5 mgm. of morphine. 

The large intestine in situ showed only depression of tone and motility 
in every one of the few observations made. K inn am an and Plant 
(1927} found this to be the case in unanesthetized dogs with colonic 
fistulae, and Schmidt (unpublished), using two such dogs, saw distinct 
decrease in tone and prolonged inhibition of motility following intra- 
muscular injection of 2 mgm. of ephedrine per kilogram, if active 
movements were present before the drug was given; if not there was 
no effect. As far as we know there has never been any sign of a 
stimulant effect by ephedrine upon the large intestine in situ. 

The results of experiments upon the gastro-intestinal tract in situ 
therefore indicate that the effects of ephedrine are, on the whole, very 
similar to those of epinephrine. With isolated strips of intestinal 
muscle, surviving in a warm saline solution, the results are much less 
uniform, some workers finding that ephedrine is only depressant, 
others reporting depression and stimulation, still others observing 
only stimulation. Thus, Amatsu and Kubota (1917) found ephedrine 
to be essentially depressant to isolated intestine of cats and rabbits, 
and the same result was obtained by To (1921), by Fujii (1925), and 
by Chen and Schmidt (1924) in rabbits. The last-named investi- 
gators found that the inhibitory effect of ephedrine could be readily 
overcome by means of pilocarpine or barium, and was not prevented 
by nicotine, thus showing that the effect was not due to depression 
of parasympathetic nerve endings, muscle fibers, or intrinsic ganglia 
(plexus of Auerbach). Subsequent workers have failed to confirm 
these results. Nagel (1925) found ephedrine to be purely stimulant 
to the isolated intestine of the rabbit and cat; the inhibitory effect 
of epinephrine could be overcome by ephedrine. Kreitmair (1927) 
found the isolated intestine of the cat to be relaxed by low concen- 


trations (1:1,000,000 to 1:100,000) of ephedrine, but slightly stimu- 
lated by a stronger one (1 : 6,000) ; the latter effect could be prevented 
completely by atropine. Reinitz (1928) reported that isolated rabbit 
intestine was sometimes inhibited, often stimulated, sometimes inhi- 
bited and then stimulated, by the same concentration of ephedrine; 
he stated that atropine had no significant influence upon the stimu- 
lant response. M6hes and Kokas (1929) reported stimulation of 
isolated rabbit intestine by weak concentrations (1:150,000 to 
1:50,000) of ephedrine, relaxation with a stronger one (1:10,000). 
Rudolf and Graham (1927) found only slight and transitory depres- 
sant effects by ephedrine upon isolated rabbit intestine. Lim and 
Chen (1928) noted only stimulation of cat intestine, isolated but 
with intact circulation, upon the addition of ephedrine. De Eds, 
Rosenthal, and Voegtlin (1928) reported pure stimulation of rabbit 
intestine exposed to a 1:5,000 solution of ephedrine, and Halsey 
(1928) found no instance, among many preparations of isolated rabbit 
intestine, of anything but stimulation by ephedrine. 

Isolated large intestines of the rabbit were found by Kreitmair ( 192 7) 
to be affected like the small by ephedrine, i.e., they were depressed 
by weak solutions, stimulated by strong ones and the latter effect could 
be prevented by atropine. Thienes (1929) reported that epinephrine 
depression of isolated large intestines of cats, rabbits, dogs, rats and 
guinea-pigs was antagonized by ephedrine. 

It may safely be assumed that any of these preparations would have 
been inhibited by epinephrine, so that it is very evident that the effects 
of ephedrine upon isolated muscle of the gastro-intestinal tract are 
inconstant. A probable explanation for this will be presented later 
(page 52) . It should be pointed out here that the effects of ephedrine 
upon movements of the gastro-intestinal tract in situ appear to be 
much more nearly like those of epinephrine than is the case when the 
two agents are tested upon isolated muscle preparations. The reason 
for this is unknown: it is possible that central nervous influences or 
indirect actions through the suprarenal glands (see page 55) play a 
part in these effects of ephedrine in the living animal. Whatever the 
explanation, the effects upon the gastro-intestinal tract in situ are 
those which are of therapeutic importance, and there is no evidence 
at present that ephedrine can properly be employed as a stimulant 
to gastro-intestinal motility. 


c. Uterus. All of the data available at present were obtained -with 
isolated tissue excepting a few experiments of Chen and Schmidt 
(1924), who found that the dog's uterus in situ was stimulated by 
ephedrine. To (1921) reported that the isolated uterus of the rabbit 
or rat was depressed by dilute solutions of ephedrine (1:20,000 and 
1 : 100,000 to 1 : 10,000 respectively), while stronger solutions (1 : 10,000 
and 1:3,300 to 1:^2,000 respectively) caused stimulation. Chen and 
Schmidt (1924) found that the isolated rabbit uterus was uniformly 
stimulated by ephedrine, with only one exception the uterus of a 
recently delivered rabbit. Stimulation was the only effect of ephe- 
drine upon isolated uterus in the experiments of Fujii (1925) on rabbits, 
of Nagel (1925) on guinea pigs, of Kreitmair (1927) on rabbits, of 
De Eds and Butt (1927) and De Eds, Rosenthal, and Voegtlin (1927) 
on rabbits and guinea-pigs, of Thienes (1929) on cats, rabbits, dogs, 
rats and guinea-pigs, of Reinitz (1928) on rabbits, and of Curtis (1929) 
on guinea-pigs and cats. The uterus of the albino rat, however, is 
uniformly relaxed by ephedrine (Liljestrand, 1927). 

These results are quite unlike those obtained with epinephrine, which 
usually relaxes the isolated non-pregnant uterus of the cat and fre- 
quently relaxes the non-pregnant guinea-pig uterus. In fact Thienes 
(1929) found that ephedrine prevented the inhibitory effect of epineph- 
rine upon various uteri. Reinitz (1928) reported that very small 
quantities of ephedrine augment the (stimulant) effect of epinephrine 
upon the isolated rabbit uterus, but larger quantities reduce it. 

In general, the action of ephedrine upon the isolated uterus is char- 
acteristically a stimulant one, and bears no constant relation to the 
action of epinephrine. Whether the same is true of the effects upon 
the intact uterus in situ has not been determined, for no experiments 
have as yet befen made with animals whose uteri are relaxed by 

d. Urinary tract. Hofbauer (1928) tested the effect of ephedrine 
upon the isolated ureter of the pig: he found that the rate of contrac- 
tions of both circular and longitudinal muscle was increased by ephe- 
drine, and that it was occasionally possible, by means of ephedrine, 
to restore contractions after they had been arrested by sodium glyco- 
cholate; the effects of epinephrine were qualitatively the same but 
it was a much more powerful stimulant than ephedrine. His results 
have been confirmed by Roth on the dog's ureter. 


Macht (1929) studied the effects of ephedrine upon the trigonal 
and fundus portions of the urinary bladders of rabbits, cats and rats. 
It has been shown repeatedly that epinephrine causes contraction of 
the trigone and relaxation of the fundus. Ephedrine caused con- 
traction of both portions. Liljestrand (1927) obtained the same 
results with the rabbit's bladder. 

e. Bronchi. One of the most useful therapeutic actions of ephe- 
drine is its ability to relieve or to prevent the paroxysms of asthma. 
Animal experimentation has shown from the start that ephedrine, 
like epinephrine, is able to relax bronchial spasm induced by various 
poisons. Amatsu and Kubota (1917) were the first to demonstrate 
this effect in rabbits whose bronchi had been thrown into spasmodic 
contraction by means of pilocarpine, muscarine, or peptone. They 
also found that isolated bronchial muscle of the cow was relaxed 
by ephedrine, even in such low concentration as 1 in 80,000. These 
results led them to recommend ephedrine in the treatment of asthma. 
Chen and Schmidt (1924) observed relaxation of the bronchial spasm 
produced by physostigmine in a dog, and stated that the effect of 
ephedrine was weaker than that of epinephrine. Kreitmair (1927), 
Villaret, Justin-Besancon, and Vexenat (1929), and Swanson (1929) 
have confirmed these results by various methods, but Halsey (1928) 
reported only exceptional bronchodilatation by ephedrine. It is 
generally agreed that ephedrine may fail to relax bronchial spasm 
when epinephrine is effective. It is generally assumed that the 
bronchodilator action of ephedrine is analogous to that of epinephrine 
and is due to stimulation of sympathetic nerves, which are inhibitory 
to this muscle; this has not, however, been definitely proved to be 
true. The effect is largely if not wholly peripheral, for it is elicited 
in excised tissue and in pithed animals. 

5. Action on secretions 

a. Saliva. Grahe in 1895 studied the action of ephedrine and 
pseudoephedrine on the submaxillary flow in a dog and found that the 
first intravenous injection has no effect while repeated injections 
gradually diminish the flow. Chen and Schmidt, and Chen investi- 
gated the same question in a series of dogs. In anesthetized animals, 
ephedrine in a dosage of 1 to 2 mgm. per kilogram produces inconsistent 


results. Occasionally it increases the submaxillary flow, and this 
occurs in spite of atropinization, but in the majority of cases it has 
no effect. Larger doses (25 mgm. per kilogram or more) in non- 
anesthetized dogs may cause profuse salivation. When a dose 
slightly below the M.L.D. is administered, the increase in salivary flow 
is a constant feature. 

b. Gastric secretion. Chen in Lim's laboratory studied the action 
of ephedrine on the gastric secretion in dogs with Pavlov or Heiden- 
hain pouches. Ephedrine injected subcutaneously unmistakably in- 
creases the gastric secretion both in volume and in acidity, although 
to only a small extent. There is no difference between the Heidenhain 
and Pavlov preparations. 

c. Pancreatic secretion. In anesthetized dogs with a cannula in the 
pancreatic duct ephedrine, given intravenously, does not change the 
pancreatic secretion, as shown by Chen. In non-anesthetized dogs 
with a pancreatic fistula, subcutaneous injections of ephedrine also 
gave negative results. Fonseca and Trincao (1928) reported that 
ephedrine caused decrease in pancreatic secretion. 

d. Intestinal secretion. Dogs with Thiry-Vella fistula do not show 
any response in their intestinal secretions to the subcutaneous injec- 
tion of ephedrine, as reported by Chen. 

e. Bile. In acute experiments with anesthetized dogs, there is no 
demonstrable alteration of bile flow after ephedrine injected intra- 
venously (Chen) . The same can be said for non-anesthetized animals 
with a pancreatic biliary fistula when ephedrine is injected subcu- 
taneously. Kreitmair, using larger doses (50 to 100 mgm. per dog), 
found an increase of bile flow from the biliary fistula, with a reduction 
of the dry matter. The increase in volume continues for more than 
three days. 

/. Sweat. Chen and Schmidt determined the sweat secretion of an 
anesthetized cat and could not detect any increase after ephedrine 
was injected into the paw. Kreitmair arrived at the same conclusion. 

In men a therapeutic dose of ephedrine occasionally produces 
diaphoresis. It is interesting to note that perspiration caused by the 
use of Ma Huang, firmly believed in by the Chinese and described by 
Li Shih-Cheng in his Pentsao Kang Mu, although not experimentally 
proved in animals, has been clinically confirmed in many reports. 


g. Lymph. With the cooperation of M. Kayumi, Chen and Schmidt 
studied the influence of ephedrine on lymph flow, collected from the 
thoracic duct of anesthetized dogs. It regularly causes an increase 
in lymph, which reaches its maximum about 15 minutes after the 
intravenous injection. 

h. Urine. In anesthetized dogs the urine flow appears to follow 
the plethysmograph of the kidney volume, as observed by Chen and 
Schmidt. There is suppression during the primary vasoconstriction, 
but an increase during the secondary dilatation. After repeated 
doses the urine is invariably suppressed. Intact rabbits which receive 
daily intravenous injections of ephedrine show a well marked diuresis. 
Starr, cooperating with T. G. Miller, studied the output of urine in a 
series of 16 men, in correlation with the systolic blood pressure. He 
divided his results into three groups: (1) those showing a rise of blood 
pressure without diuresis and with albuminuria; (2) those showing no 
rise in pressure with no diminution of urine and no albuminuria; and 
(3) those showing a rise of pressure with diuresis and albuminuria. 
The occurrence of albumin in the urine is transitory, for it disappears 
when the effect of the ephedrine wears off. In those that show an 
increase in pressure but no diuresis, the albuminuria is due to renal 
vasoconstriction, while in those that show rise in pressure and increase 
in urinary output, it is probably due to the alternate constriction and 
dilatation of the glomerular functional units. Kreitmair observed 
diuresis on himself after the ingestion of 50 mgm. of ephedrine, lasting 
for 2 to 3 hours. Gradinescu and Marcu also call attention to the 
fact that the variation in urine flow depends on vascular changes. 

6. Action on the blood 

a. Blood cells. Hess reported leucocytosis after ephedrine, reaching 
its maximum at the same time as the blood pressure attains its highest 
level. Marcu and Petresco studied the blood changes in men on 
intravenous injection of ephedrine. A dose of 20 mgm. increases the 
leucocytes within the first five minutes, lasting for more than one hour 
and 40 minutes. The leucocytosis consists chiefly of lymphocytosis. 
The red blood corpuscles are also increased, with a corresponding 
increase in hemoglobin. The maximum is attained in about 40 min- 
utes. Ephedrine in a dosage of 60 mgm., given intravenously, pro- 


duces a leucocytosis and erythrocytosis which, lasts for two hours or 
longer. These changes, the authors believe, indicate a concentration 
of the blood. Pathological conditions apparently modify this reaction. 
Thus, Marcu and Petresco observed with a dose of 20 mgm. intra- 
venously a decrease of red blood corpuscles and leucopenia in a case 
of Addison's disease, and leucopenia but erythrocytosis in a case of 
Hodgkin's disease. Binet, Arnaudet, Fournier and Kaplan observed 
an increase in platelets hi addition to erythrocytosis and leucocytosis 
hi chloralosed dogs. The maximal increase in the platelets is reached 
at the end of 5 to 15 minutes after the intravenous injection of 3 mgm. 
of ephedrine per kilogram. According to these investigators the 
increase in the formed elements of the blood is due to contraction of the 
spleen, for splenectomy prevents this reaction and previous adminis- 
tration of yohimbine, which paralyzes the contractors of the spleen, 
abolishes such a response. 

b. Blood chemistry. Chen and Schmidt studied the effect of ephe- 
drine on the blood sugar in two anesthetized dogs. Their results 
were inconclusive. Negative or doubtful results were obtained by 
T. G. Miller in men, by Hess in men, by Kreitmair in rabbits, by 
Rudolf and Graham in diabetics, by Tu in men, and by Haintz in 
men. Hyperglycemia may be produced in animals by doses larger 
than the pressor ones. Thus, Nagel determined the hyperglycemic 
dose in rabbits to be 25 mgm. per kilogram, injected intravenously. 
Wilson found it to be 10 to 15 mgm. per kilogram (intravenously 
or subcutaneously) in dogs, and 20 to 30 mgm. per kilogram (intra- 
venously) in rabbits. According to Nitzescu, hyperglycemia occurs 
in dogs when they are in full digestion but is absent when they 
are previously starved. The doses he used were 0.5 to 3.0 mgm. 
per kilogram, given intravenously. The simultaneous administra- 
tion of glucose and ephedrine does not increase the hyperglycemia 
produced by glucose alone but lengthens its duration. A limited 
increase in blood sugar in men with therapeutic doses (5 to 100 mgm.) 
of ephedrine given orally was observed by Pollak and Rabitschek and 
by Lublin. Radoslav and Stolcesco administered ephedrine to men by 
intravenous injection. Doses of 5 to 90 mgm. produce a diphasic 
reaction a primary hyperglycemia followed by hypoglycemia. The 
blood sugar returns to normal in about two hours. 


After the intravenous injection of 20 mgm. of ephedrine, the serum 
albumin increases to the extent of 10 parts per thousand and returns 
to normal in 20 minutes, while the globulins are increased for two 
hours, as determined by Marcu and Petresco. The concentration of 
albumins and globulins occurred in both healthy individuals and in a 
case of Addison's disease and another of Hodgkin's disease. Unlike 
epinephrine, ephedrine does not raise the peptidase titer of the rabbit's 
serum (Pfeiffer and Standenath). 

7. Action on metabolism 

a. Metabolic rate. T. G. Miller reported an increase in metabolic 
rate in 4 cases with 100 to 125 mgm. of ephedrine injected subcu- 
taneously. Rowntree and Brown also studied the calorigenic effects 
of ephedrine, given by mouth, in several diseased conditions. In 3 
cases of Addison's disease there was an increase in metabolic rate in 
two but a decrease in the third. In a case of questionable Addison's 
disease and 4 cases of hypotension, an increase was also demonstrated. 
The effects seem to be transitory and an hour afterwards there may be 
a tendency to a fall of metabolic rate. A patient with endocrine 
obesity showed a decrease of 1 1 points with SO mgm., but with 100 mgm. 
there was an increase of 13 points in 3 hours. In a case of pituitary 
tumor there was a demonstrable increase of the basal metabolic rate 
after 50 mgm. of ephedrine had been given. In rabbits, Duliere 
observed only inconsistent changes in metabolism after the adminis- 
tration of ephedrine. 

b. Gaseous exchange. Schmidt (1928) demonstrated that ephedrine 
increases both cerebral 2 consumption and COa liberation. Wilson, 
Pilcher and Harrison, and Halsey, Reynolds and Blackberg also 
observed an increase in 2 consumption with a tendency of the alveolar 
CC>2 to fall. After giving fructose or glucose, the R.Q. is always 
greater than 1, but if ephedrine and fructose are given at the same time 
the R.Q. becomes less than 1. According to Lublin, this means the 
inhibition of fat formation by ephedrine. In rabbits, Dulie're con- 
stantly observed a decrease of R.Q. following the intravenous injec- 
tion of ephedrine. 

c. Body temperature. With toxic doses Miura in 1887 reported an 
elevation of temperature in dogs, rabbits and mice. Like epinephrine 


and jS-tetrahydronaphthylainine, ephedrine, according to Hashimoto 
(1915), slightly raises the body temperature (0.5 to 0.7C.) in normal 
rabbits and it produces fever in those animals whose heat centers have 
been punctured. The dose for the production of this response is 20 
mgm. per kilogram. Notwithstanding, Suzuki recently reported a 
slight fall in rectal temperature in rabbits, either normal, adrenalec- 
tomized or with the splanchnic nerves sectioned, using a dose of 30 
mgm. per kilogram, given intravenously. 

8. Action on the central nervous system 

Ephedrine appears to stimulate the central nervous system. Airila 
in 1913 showed that chloralized rabbits can be awakened temporarily 
by an intravenous injection of ephedrine (10 to 20 mgm.). Morita in 
1915 obtained similar results in rabbits whose cerebral hemispheres 
had been removed, and believes that the stimulation is subcortical. 
In the squid, Loligo pealii, doses of 5 mgm. or more make it turn 
blood-red within half an hour, the color persisting for twelve to twenty 
hours or more, as observed by Nadler. Oral administration and injec- 
tion into the circulation via the heart likewise produce this dark 
coloration. The author attributes this change to stimulation of the 
central nervous system. In men moderate doses of ephedrine some- 
times cause tremor, nausea, and insomnia, which in all probability is 
due to stimulation of the central nervous system. C. F. Schmidt 
obtained evidence that ephedrine directly stimulates the respiratory 
center. In anesthetized dogs, Johnson and Luckhardt found that 
ephedrine in large doses, injected intravenously or subcutaneously, 
causes a marked increase in the reflex excitability of the spinal cord, 
as measured by the knee jerk. The action is not dependent on any 
influence of the higher centers on the cord nor due to the hemodynamic 
action of the drug, since the increase in excitability of the cord out- 
lasts the rise of blood pressure. 

9. Action on the peripheral nerves and voluntary muscles 

The action of ephedrine on the motor nerves has been studied by 
Read and Lin. They conclude that ephedrine potentiates the action 
of novocaine on the frog's sciatic nerve. By the addition of 0.005 
per cent of ephedrine to a 1 per cent solution of novocaine the tune 
required for blocking of the motor impulse is lessened by 80 per cent. 


Ogata (1920) states that ephedrine has no local anesthetic action, 
meaning that it is devoid of action on the sensory nerve endings. 
Read and Lin, on the other hand, claim that a mixture of ephedrine 
with epinephrine and potassium sulphate can produce, by the wheal 
method, local anesthesia equal in intensity to that produced by a 
mixture of similar proportions and strengths of novocaine, epinephrine 
and potassium sulphate. 

Amatsu and Kubota (1917) studied the effect of ephedrine on the 
frog's gastrocnemius muscle. They found that a 0.1 per cent solu- 
tion raises the threshold of stimulation (electric) and produces irregu- 
lar contractions on repeated stimulation with a current of constant 
strength, instead of a gradual fatigue curve. 

10. Mode of action 

In a previous review of this subject, Chen and Schmidt (1926) 
divided the actions of ephedrine into three categories: the thera- 
peutically useful ones, which are due to peripheral sympathomimetic 
effects; the stimulant action upon the central nervous system; and the 
depressant action upon heart muscle. The second and third types of 
action were said to be exerted as a rule only by excessive dosage and 
were regarded as undesirable or dangerous . Subsequent developments 
have necessitated a modification in this characterization in so far as 
the central nervous effects are concerned, for it is now certain that 
they may be elicited by therapeutic doses in some individuals at least, 
and may be useful in combating the action of narcotic poisons, 
particularly upon the respiratory center. The action of ephedrine 
upon the brain cells has not been analyzed, but it appears to be com- 
parable with that of caffeine (Schmidt, 1928). The depressant action 
upon heart muscle is essentially similar to that of any other myocardial 
depressant, and the only practical importance of this type of effect 
is that it imposes upon the therapeutic usefulness of the 
drug. There is no disagreement among various workers with respect 
to the central nervous and myocardial depressant effects of ephedrine. 
The peripheral actions of ephedrine, which are of greatest interest 
to the clinician, are not so simply disposed of. The earliest workers 
in this field (Amatsu and Kubota, 1917; To, 1921; Chen and Schmidt, 
1924) were impressed with the obvious similarity of the effects of 


ephedrine to those of epinephrine, and concluded that ephedrine is 
a sympathomimetic substance. These effects include mydriasis with 
preservation of light and accommodation reflexes, broncho-dilatation, 
cardiac acceleration and augmentation, vasoconstriction, inhibition 
of gastro-intestinal motility (hi many cases), hyperglycemia, and 
occasional secretion of saliva by the atropinized submaxillary gland. 
In fact no other explanation is possible for these effects, taken as a 
whole. The question is not whether ephedrine produces sympa- 
thomimetic effects but whether its important effects are due wholly 
or even largely to such actions. During recent years considerable 
evidence having been obtained, by a number of investigators, that the 
peripheral effects of ephedrine differ qualitatively in some respects from 
those of epinephrine, the conclusion has been drawn that ephedrine 
owes some of its effects to direct excitation of smooth muscle, irre- 
spective of sympathetic innervation. Those who have concluded that 
ephedrine acts at least partly upon muscle fibers include Nagel (1925), 
De Eds (1927), De Eds and Butt (1927), Pak and Read (1928), 
M6hes and Kokas (1929) , and Halsey (1928) . The question has more 
than theoretical importance, for if this conclusion is fully justified 
ephedrine should be looked upon as a drug with the clinical usefulness 
of pituitrin rather than that of epinephrine. 

Decisive evidence upon a point of such fundamental importance as 
this might well be sought in investigations of the action of the drug 
upon simple organisms or preparations. The only pertinent investi- 
gation of the action of ephedrine upon a lower form of lif e is that of 
Nadler (1927), which has already been discussed (page 16). He 
concluded that ephedrine is essentially sympathomimetic, not mus- 
culotropic. However, the organism used by him is relatively complex, 
and the exact mechanism of the responses studied has not been estab- 
lished. The results seem to the reviewers to be suggestive but not 
conclusive evidence upon the point at issue. 

A relatively uncomplicated preparation of mammalian tissue is the 
plexus-free strip of small intestine of the cat (Gasser: Journ. Phar- 
macol. Exper. Therap., 1926, xxvii, 395). This apparently has not 
been used to test the musculotropic power of ephedrine. One of the 
reviewers (S.) recently tested 12 such preparations with ephedrine. 
In no case was there any trace of stimulation, and depression was more 


commonly observed with ephedrine than with epinephrine. The 
number of observations was small, but all the preparations were active, 
and it is reasonable to suppose that a conspicuous musculotropic action 
would have been disclosed if present. These results lend no support 
to the conception that ephedrine is musculotropic. In fact they 
suggest rather that the direct action of ephedrine upon smooth 
muscle is a depressant one, since ephedrine was more uniformly in- 
hibitory than epinephrine. 

Another suitable test-object would be blood vessels which are not 
conspicuously affected by epinephrine, such as those of the coronary, 
cerebral, and pulmonary areas. The only available information 
concerning the action of ephedrine upon such structures is the state- 
ment of Chen and Schmidt (1924) that coronary outflow from the 
perfused mammalian heart was augmented, never decreased, by 
ephedrine. This is far from conclusive evidence upon the point at 
issue, since rate and force of cardiac contractions were also increased. 
However, pituitrin regularly causes very marked reduction in coro- 
nary flow in such preparations. If the latter is regarded as a repre- 
sentative example of the effect of musculotropic agents, the result 
with ephedrine indicates that the latter is not musculotropic. Further 
information concerning the actions of ephedrine upon coronary, 
cerebral, and pulmonary vessels is highly desirable. 

The contention that ephedrine is capable of exerting stimulant 
effects upon smooth muscle fibers irrespective of their innervation is 
based upon observations of two general sorts. These are, the influence 
of certain other substances (ergotoxine, yohimbine, cocaine, insulin) 
upon the circulatory effects of ephedrine, and the action of ephedrine 
upon various preparations of isolated smooth muscle. None of the 
evidence so far obtained by these procedures appears to be decisive. 

a. Circulatory responses. The fact that ergotoxine (ergotamine) 
leads to a reversal of the blood pressure effect of epinephrine has led to 
the employment of ergotoxine as a means of discriminating between 
sympathomimetic and musculotropic effects on the part of other drugs 
which raise blood pressure. Other things being equal, a given quan- 
tity of the agent being tested should cause a fall in pressure after 
ergotoxine if it is sympathomimetic, while if its effects are unaltered 
by ergotoxine it must be musculotropic. 


Among those who have tested the influence of ergotoxine upon the 
pressor response to ephedrine are Nagel (1925), Kreitmair (1927), 
De Eds and Butt (1927), Chen (1928), and Curtis (1929). All found 
that the pressor effect of ephedrine was reduced by ergotoxine, but 
Curtis was the only one who reported complete absence of such effect 
or an actual reversal after ergotoxine, though a reversal of epinephrine 
effects was clearly demonstrated in every case. Curtis attributed his 
success to the use of smaller quantities of ephedrine and larger doses 
of ergotoxine than had been used by his predecessors. Until this is 
confirmed, however, it appears proper to conclude that while ergo- 
toxine may diminish or even prevent the pressor effect of ephedrine, 
an actual reversal, similar to that of epinephrine, is not the charac- 
teristic result. 

These results have been interpreted as strong evidence in favor of a 
musculotropic action by ephedrine, but such conclusion is by no means 
obligatory, for two reasons: First, as has been emphasized repeatedly 
(Chen and Schmidt 1924, 1926; Chen and Meek, 1926; Chen, 1928; 
Curtis, 1928), the pressor effect of ephedrine is due more to increased 
cardiac action than to vasoconstriction, while in the case of epi- 
nephrine the reverse is true. It is well known that ergotoxine, in 
quantity sufficient to paralyze vasoconstrictor receptors and therefore 
to produce the epinephrine reversal, has much less effect upon the 
cardiac accelerator system (see Chen, 1928). It is through the latter 
system that ephedrine exerts much of its influence upon blood pressure. 
Consequently one need not expect the pressor effect of ephedrine to 
be abolished by ergotoxine until the latter is present in sufficient 
quantity to paralyze the cardiac accelerator system, and Curtis (1928) 
states that with sufficiently large doses of ergotoxine the pressor effect 
of ephedrine can be completely prevented. These objections to the 
conclusions derived from the ergotoxine experiments have been raised 
by Chen (1928) and by Curtis (1928). 

Second, it must be remembered that the epinephrine reversal by 
means of ergotoxine presupposes a powerful stimulant action by 
epmephrine upon vasodilator nerves, but there is no reason to believe 
that ephedrine possesses such an action. For, as has already been 
pointed out (page 20), the smallest effective doses of ephedrine pro- 
duce only a rise in blood pressure, and as the effects of ephedrine wear 


away blood pressure returns to normal, not to a subnormal level. 
One of the outstanding advantages of ephedrine over epinephrine as a 
constrictor of nasal blood vessels is the absence of after-dilatation in the 
case of ephedrine. There is no decisive evidence upon this point, 
but these observations suggest strongly that the effects of ephedrine 
upon blood vessels are dominantly if not exclusively motor (con- 
strictor), while in the case of epinephrine inhibitory (dilator) actions 
are conspicuous (Dale, 1906). The present situation is therefore 
practically identical with that encountered by Barger and Dale (1910) 
in their investigation of sympathorm'm etic bases. They found that 
ergotoxine reduced but did not reverse the pressor effect of amino- 
aceto-catechol or d^amino-ethanol-catechol, while it led to complete 
reversal of the effects of methylamino-catechol or dZ-epinephrine. 
The difference was attributed to a greater predominance of inhibitory 
(vasodilator) actions on the part of the latter substances, though the 
effects of all were regarded as purely sympathomimetic. The failure 
of ephedrine to produce a fall in blood pressure after ergotoxine cannot 
therefore be regarded as proof that ephedrine is not sympathomimetic. 

The above considerations probably apply also to the effects of 
yohimbine, which Raymond-Hamet (1927) found to exert an in- 
fluence like that of ergotoxine: the pressor response to epinephrine 
was inverted, while that to ephedrine was only reduced. 

Cocaine is another agent which has been used to determine whether 
a pressor drug is sympathomimetic or musculotropic, as a result of 
the work of Tainter and Chang (1927). They found that a small dose 
of cocaine augmented the pressor effect of epinephrine, but reduced 
or abolished that of tyramine, the latter being regarded as musculo- 
tropic. De Eds (1927) and Pak and Read (1928) found that cocaine 
also reduced the pressor effect of ephedrine. Chen (1928) was unable 
to confirm this conclusion; he believed that the result was due simply 
to the fact that a second dose of ephedrine is less effective than the 
first even if no cocaine is given between them. However, Tainter 
(1929) has recently shown that cocaine, in dosage which augments 
the pressor effect of epinephrine, may reduce or abolish that of 

These results have been interpreted as evidence that ephedrine is 
not sympathomimetic, but musculotropic, in its circulatory effects. 


Yet, as far as the reviewers are aware, no evidence has been presented 
that cocaine augments the effectiveness of sympathetic nerve excita- 
tion by anything but epinephrine, and this particular effect might 
well be a drug synergism, peculiar to epinephrine, with no relation to 
sympathetic stimulation per se. Nor is there any evidence that reduc- 
tion of pressor effectiveness by cocaine is an index of musculotropic 
action. In fact Tainter has recently reported (XIII International 
Physiological Congress) that cocaine neither increases nor decreases 
the effectiveness of barium and pituitrin. If one grants the validity 
of the assumption that any agent, to be sympathomimetic, must 
duplicate all of the peculiar effects of epinephrine, the cocaine test, 
like the ergotoxine one, indicates that ephedrine is neither sympatho- 
mimetic nor musculotropic. 

Another agent which modifies the circulatory response to epine- 
phrine much more than that to ephedrine is insulin. Cs6pai and 
Pinter-Kovats (1927) found that insulin prevents the pressor effect 
of epinephrine, but not that of ephedrine. The significance of this 
observation, apart from an indication that the circulatory effects of 
ephedrine are in some way different from those of epinephrine, is 
unknown to the reviewers. 

It seems to the reviewers that these various circulatory responses, 
in the present state of our knowledge, can show only whether a sub- 
stance does or does not elicit certain effects that are characteristic of 
epinephrine. If they are to be used for the purpose of determining 
whether a new drug is or is not likely to be of practical value as a 
substitute for epinephrine, one must consider the fact that ephedrine, 
which, according to all these tests, is not epinephrine-like, has amply 
proved its practical value as a substitute for epinephrine . The review- 
ers do not believe, therefore, that absence of epinephrine-like responses 
in the ergotized or cocainized animal can be regarded as convincing 
evidence of lack of sympathomimetic action on the part of other 

b. Effects upon smooth musfle. In considering the work that has 
been done upon this subject (pages 33-40) it was pointed out that 
the effects of ephedrine upon uterus and bladder fundus appear to be 
uniformly stimulant, though epinephrine may be depressant; that 
the surviving small intestine may be stimulated or depressed by ephe- 


drine though invariably depressed by epinephrine. Apparently the 
only smooth muscles that are uniformly relaxed in vitro by ephedrine 
are found in the bronchi, the sphincter pupillae and the uterus of 
the albino rat. While it is somewhat difficult to see why a substance 
which acts directly upon smooth muscle fibers should stimulate some 
and depress others, it is equally difficult to see why a substance which 
owes its effects to sympathomimetic actions should so frequently lead 
to contraction of structures that are relaxed by epinephrine. 

Considering first the isolated small intestine, however, a reason for 
this discrepancy is readily found in an action by ephedrine upon motor 
ganglia as well as inhibitory endings. Chen and Schmidt (1924, fig. 5) 
showed a tracing which illustrated the epinephrine-like effect of ephe- 
drine after the ganglia had been paralyzed with nicotine. This proce- 
dure has recently been repeated by one of the reviewers (S.) with pre- 
parations made from the small intestines of cats, dogs, and rabbits, and 
the results have been uniformly like the earlier ones. In no instance 
did ephedrine fail to exert a typical sympathomimetic effect after 
nicotine, while stimulation of strips from adjacent parts of the bowel 
was frequently observed when ephedrine was applied before nicotine. 
Reference has also been made (page 47) to the uniform absence of 
stimulant effect by ephedrine upon plexus-free preparations of small 
intestine. It appears, therefore, that the intestinal effects of ephe- 
drine consist in a combined stimulation of ganglia (plexus of Auer- 
bach), which causes increased motility, and of inhibitory sympathetic 
endings. When the ganglionic action is excluded by means of nico- 
tine or removal of the plexus, the sympathomimetic action is clearly 
and uniformly manifested. 

In the case of the uterus, the corresponding information is not 
available. Ephedrine is almost invariably stimulant to isolated uteri, 
whether epinephrine is stimulant or inhibitory, and this argues in 
favor of the musculotropic or pituitrin type of effect. Ergotoxine 
has been added to the solution in which the uterus was immersed, 
by Nagel (1925), Kreitmair (1927), De Eds and Butt (1927), Reinitz 
(1928), and Curtis (1929). This substance should paralyze motor 
sympathetic nerve endings, and uteri so treated were uniformly 
inhibited by epinephrine, but all observers except Curtis reported that 
ergotoxine did not prevent the stimulant action of ephedrine: he 


stated that by means of large doses of ergotoxine the effects of ephe- 
drine could be prevented though never reversed. It may be, there- 
fore, that the effects of ephedrine upon the isolated uterus are indeed 
sympathomimetic, but are exerted mainly if not exclusively upon 
motor parts of the .system, the inhibitory parts being affected much 
less or not at all an analogy to the effects upon blood vessels. 

The stimulant action of ephedrine upon the intestine being appar- 
ently similar to that of nicotine (i.e., ganglionic), a similar action upon 
the uterus may be regarded as a possibility. This has not been investi- 
gated. It is not possible at present to make a plexus-free preparation 
of uterine muscle. The effects of nicotine upon the uterus (virgin 
organ of the cat) were found by Barger and Dale (1910) to be inhibi- 
tory in vivo but stimulant in vitro. In current terminology, this 
would imply that nicotine is sympathomimetic in vivo, musculotropic 
in vitro. Barger and Dale, however, believed that the inhibitory effect 
in vivo was due to stimulation of sympathetic ganglia which rapidly 
lose their sensitivity when the uterus is excised. They did not explain 
the stimulant action in vitro, but it can scarcely be called musculo- 
tropic because nicotine does not stimulate ganglion-free smooth muscle 
of the intestine (Gasser, 1926). 

The situation appears to be rather obscure, and the reviewers 
believe that the true explanation of the uterine effects of ephedrine 
can be given only when more is known about the intrinsic innervation 
of the organ. 

The situation with respect to the urinary bladder muscle is much 
the same. The only data are those of Macht (1929) and Liljestrand 
(1927) (see page 40, above). These effects of ephedrine are like 
those of pituitrin, unlike those of epinephrine. The results are 
equivocal evidence for or against a musculotropic action by a drug that 
appears to affect certain ganglia as well as endings, and to stimulate 
motor sympathetic nerves more powerfully than inhibitory ones. 

It has been claimed by Fujii (1925), Kreitmair (1927), Reinitz 
(1928), and Marcu and Savulesco (1928) that ephedrine stimulates 
both parasympathetic and sympathetic nervous systems, but the 
evidence presented hi support of this contention is inconclusive. 
Fujii (1925) believed that the constrictor action of ephedrine upon 
perfused blood vessels of the frog was exerted through parasympathetic 


nerve structures, since it was absent when atropine was added to the 
perfusion fluid; however, it is well known that atropine has a vaso- 
dilator action of its own hi such circumstances (Cushny, Textbook of 
Pharmacology, 1928, p. 347). Fujii, as well as Reinitz (1928), found 
that atropine prevented the stimulant action of ephedrine upon the 
isolated uterus, but this has not been the case in the experience of the 
reviewers. Kreitmair (1927) reported that the stimulant action of 
ephedrine upon isolated intestine was prevented or abolished by 
atropine, but this is denied by Reinitz (1928). M6hes and Kokas 
(1929) claim that atropine partly prevents the depressant action of 
ephedrine upon the perfused frog's heart, but this is opposed to the 
results of Fujii (1925) and Kreitmair (1927). 

Apparently there is no better agreement concerning the preferential 
action of ephedrine, assuming that it acts upon both nervous systems. 
Kreitmair (1927) believed that minimal doses affected only the 
sympathetic, and that the parasympathetic was influenced only by 
relatively high concentrations. Marcu and Savulesco (1928), how- 
ever, claim that minimal quantities stimulate the parasympathetic 
preferentially, while with large doses sympathetic stimulation domi- 
nates the picture, the effects of intermediate dosages being antagonistic 
and therefore inconstant or absent. 

Further work is needed before this point can finally be settled. The 
conflicting opinions indicate that ephedrine certainly has no con- 
spicuous pilocarpine-like effects, and Reinitz (1928) claimed that it 
actually has an atropine-like effect upon the intestine. There is no 
reason therefore for employing ephedrine as a parasympathetic 

As to the exact site of ephedrine actions, there is little information. 
Chen and Schmidt (1924) pointed out that ephedrine was able to 
dilate the pupil whose sympathetic (pupillo-dilator) innervation had 
degenerated following extirpation of the ganglion, while cocaine was 
ineffective. They concluded that the point of action of ephedrine was 
apparently peripheral to that of cocaine, the absence of effect from the 
latter indicating degeneration of the structures upon which it acted. 
Marcu and Gheorghiu (1927) have recently shown that ephedrine is 
able to increase the rate of a heart whose accelerator nerves have 
degenerated following removal of the ganglia: this also points to an 


action upon structures peripheral to the finest nerve fibrils, which 
degenerate when the ganglion is removed. On the other hand, there 
is no good reason to attribute any of the peripheral effects of ephedrine 
to direct action upon effector substance (muscle fibers, gland cells). 
This makes the situation comparable to that encountered with epineph- 
rine, and leads to the conclusion that ephedrine likewise acts upon 
hypothetical myoneural junctions. 

However, there is reason to believe that the myoneural junctions 
affected by ephedrine are not the same as those affected by epineph- 
rine, in the pupillo-dilator system at least. Reference has already 
been made (page 34) to a few observations which indicate that 
denervation does not sensitize the pupil to ephedrine, but rKTninishes 
its effectiveness. Should this be confirmed, it would suggest that 
some of the ephedrine receptors degenerate after denervation, as 
all of those for cocaine appear to do. This would imply that the 
point of action of ephedrine upon the pupil is at least partly central 
to that of epinephrine, and partly peripheral to that of cocaine. 

It has been suggested by several workers that many of the pe- 
culiarities in the action of ephedrine could be explained on the basis 
of an increased secretion of epinephrine by the suprarenal glands as a 
result of absorption of ephedrine. This would account for the effects 
of ephedrine upon metabolism, blood sugar, etc. and for epinephrine- 
like effects upon small intestines in situ, not in vitro. The question 
has a practical significance in connection with the treatment of Addi- 
son's disease. 

Evidence upon this point is somewhat contradictory. Nagel (1925) 
reported that suprarenalectomy did not reduce, but seemed to augment 
the pressor effectiveness of ephedrine. Chen and Schmidt (1926) 
stated that removal or ligation of the suprarenal glands did not 
diminish, the pressor effect of ephedrine. It seems dear, therefore, 
that the circulatory effects of ephedrine are not due wholly to stimula- 
tion of the suprarenal glands. 

On the other side, Suzuki (1928) found that a given dose of ephedrine 
produced a smaller and briefer rise in blood pressure in unanesthetized 
rabbits whose splanchnic nerves had been cut or whose suprarenal 
glands had been removed, than it did in normal controls. Section of 
the splanchnics reduced the effectiveness of ephedrine more than 


suprarenalectomy did, which suggests that part of the influence of 
ephedrine upon the suprarenals must be exerted through the nervous 
system. Gradinesco and Marcu (1927) found that a small quantity 
(0.1 to 0.2 cc. of a 1 per cent solution) of ephedrine, injected directly 
into the suprarenal capsules of dogs anesthetized with chloroform, 
caused a marked and sustained rise in blood pressure. To reproduce 
the effect by intravenous injection of ephedrine, 7 to 10 tunes the 
quantity was required. They reported also that removal of the 
supra reiuils led to marked reduction in the pressor effectiveness of 
ephedrine, which is opposed to the results reported by Nagel (1925) 
ami by Chen and vSchmidt (1926). Houssay and Molinelli (1927) 
employed a crosscd-circulation (suprarenalo-jugular anastomosis) 
preparation in dogs. They reported that large doses (40 to SO mgm. 
per kilogram) of ephedrine caused increased suprarenal output in six 
out of ten attempts. The effect was abolished by section of the 
splanchnic nerves, and was therefore presumably due to an action 
ujjon the nervous system- - a conclusion which is like that of Suzuki 
( 1928). It must be noted, however, that the doses of ephedrine used 
by Suzuki (30 mum. per kilogram) and by Houssay and Molinelli 
(40 to 50 mgm. per kilogram) are so close to the toxic level that 
nervous effects are to be expected. Only the results of Gradinesco 
and Marcu point to the possibility of a suprarenal stimulation by 
small quantities of ephedrine, and these could scarcely be regarded as 
small when they were injected directly into the gland. 

It appears that ephedrine is probably capable of stimulating the 
suprarenal glands, but whether the effect can be elicited by ordinary 
doses or is exerted only by toxic quantities has not been determined. 
It is certain that an action of this sort cannot account for all of the 
effects of ephedrine, for some of these are elicited upon local application 
(pupil), others are demonstrable in excised tissues (heart, perfused 
blood vessels, isolated smooth muscle) . Clinical experience has shown 
that ephedrine has no beneficial influence upon the course of Addison's 
disease. However, since the pathological process is a progressive one 
which ephedrine could not be expected to check, this does not prove 
that the drug had not stimulated the residual normal tissue. 

The above discussion concerning the mode of action of ephedrine 
can be summarized as follows: 


There is no valid evidence that ephedrine is capable of directly 
stimulating any smooth muscle, while there is some direct evidence 
that it cannot do so (chromatophores of the squid, plexus-free and 
nicotinized intestine, albino rat uterus). 

There is reason to suspect that ephedrine stimulates motor sympa- 
thetic nerves more powerfully than inhibitory ones when both are 
present in the same tissue (blood vessels, perhaps uterus and bladder), 
and possibly the inhibitory set is not affected at all by ephedrine; but 
when the sympathetic innervation is purely inhibitory ephedrine seems 
uniformly to stimulate it (bronchi, isolated sphincter pupillae, isolated 
intestine nicotinized, plexus-free, sometimes intact). 

Ephedrine appears to stimulate certain ganglia (cardiac accelerator, 
plexus of Auerbach), but whether this is a general effect or is limited 
to these localities has not been determined. 

Its peripheral effects have not been shown definitely to involve the 
parasympathetic system, unless the plexus of Auerbach is regarded 
as a part of the latter. Ephedrine certainly has no conspicuous 
pilocarpine-like actions, and its important effects are not prevented 
by atropine. 

There is no conclusive evidence that ordinary therapeutic doses of 
ephedrine stimulate the suprarenal gland, or that any of the effects 
of such doses are so caused. 

The point of action of ephedrine upon the pupil appears to be central 
to that of epinephrine, peripheral to that of cocaine, i.e., peripheral 
to the finest anatomically demonstrable nerve fibers. 

As to the precise mode of action, one can, in the present state of our 
knowledge, only characterize it by one of two general, descriptive 
terms sympathomimetic or musculotropic. The first, according to 
the definition of Barger and Dale (1910), who introduced it, implies 
that the effects of the drug are analogous to those of excitation of the 
sympathetic nervous system by other agencies, such as electrical 
stimulation. The second is currently used to designate a group of 
drugs and poisons which stimulate smooth muscle indiscriminately 
and irrespective of its innervation. The outstanding example of the 
first group is epinephrine, while of the second pituitrin and barium 
are representative. In the recent investigations of ephedrine it has 
been tacitly assumed that epinephrine actions are the absolute 


standard of sympathomimetic effects. But tlie originators of the 
term (Barger and Dale, 1910) pointed out that in some respects the 
effects of epinephrine are unlike those of electrical excitation of the 
sympathetic as well as those of many sympathomimetic drugs, 
notably in the pronounced tendency of epinephrine to produce inhibi- 
tory effects upon blood vessels and uterus of the cat. It does not seem 
to the reviewers that, with such observations on record, it is necessary 
to restrict the group of sympathomimetic agents to those which 
duplicate the actions of epinephrine in all respects. 

Classification of ephedrine in one or the other of these categories is 
at present rather arbitrary, for the choice depends upon the definition 
of the terms. Since neither term is explanatory of the mode of reac- 
tion of drug with tissue substance, but is merely descriptive of observed 
or expected phenomena, the choice is of no great immediate impor- 
tance. However, the reviewers believe that it is better at present to 
regard ephedrine as sympathomimetic in all its peripheral effects than 
to consider it as sympathomimetic in some localities, musculotropic in 
others. This choice is based partly upon the burden of clinical evi- 
dence, which justifies the retention of ephedrine as a drug with the 
general usefulness of epinephrine, and partly upon the possibility of 
future developments. If stimulation by ephedrine of structures that 
are depressed by epinephrine is conclusive proof that ephedrine is 
musculotropic, the matter is closed, and little or nothing has been 
added by way of fundamental knowledge to utilize in investigation of 
other substances. But if search is made for an explanation of these 
discrepancies upon a sympathomunetic basis, it is reasonable to sup- 
pose that something will be added to our knowledge concerning the 
sympathetic innervation of various structures, and it is not incon- 
ceivable that progress may be made toward an explanation of the 
extraordinary predilection of many substances for the sympathetic 
nervous system, or for certain parts of it. 

It is quite possible that some of the effects of ephedrine are musculo- 
tropic. The facts remain, however, that no valid evidence exists 
that such is the case, that at least one of the supposedly musculotropic 
actions can even now be shown not to be such (i.e., the stimulant 
effect upon isolated intestine), and that the general picture of ephe- 
drine actions is strikingly similar to that resulting from st.frmi1fl.firm 


of the sympathetic nervous system by other means. The reviewers 
therefore believe it proper to await unequivocal demonstration of 
musculotropic actions by ephedrine, and the exclusion of the possibility 
of sympathetic stimulation as an explanation, before accepting the 
view that any of the peripheral effects of ephedrine are not syrnpa- 

11. Absorption and excretion 

Ephedrine is readily absorbed and produces systemic effects when 
administered orally, subcutaneously, intramuscularly, subdurally, 
intraperitoneally, or rectally in animals, and the same has been 
shown to be true of men excepting for the subdural and intraperitoneal 
routes, which have not been tried. The rate of absorption in men, 
evidenced by the rise in blood pressure, is somewhat faster following 
subcutaneous or intramuscular injection than following oral adminis- 
tration, but the degree of effect is not significantly different (Miller, 
1925); evidently absorption from the alimentary tract is complete. 
The effects of intravenous injection are much briefer than those of 
other modes of administration (Jansen). The readiness with which 
ephedrine is absorbed represents an outstanding and usually ad- 
vantageous difference from epinephrine; it may be due to a lack of 
constrictor action of ephedrine upon finer blood vessels. 

The fate of ephedrine in the body is still unknown, for there is no 
reliable and sensitive method for detecting it in tissues or excreta. It 
apparently passes through the liver unchanged but whether it is 
destroyed in the body or eliminated, in unaltered or altered form, is 
unknown, nor is anything known about the route of elimination. 

12. Toxicity 

a. Minimal lethal dose. Table 2 shows the toxicity of ephedrine 
in different animals. The order of theM.L.D. by different methods 
of administration is as follows: intravenous, intramuscular, intra- 
peritoneal, subcutaneous, and oral. The drug is therefore most toxic 
by intravenous injection and least toxic by mouth. In general, differ- 
ent workers agree that ephedrine has a low toxicity and a wide margin 
of safety. In dogs, for example, the optimal pressor dose intra- 
venously is 1 to 10 mgm. per kilogram while the M.L.D. by the same 



Toxtcity of ephedrine in different animals 






Squid (Loligo pealii) . . . 
Froff ' 





mgm per 



Amatsu and 

Hamster . . . . . 


Tn traperitoneal 


Pak and Read 
Pak and Read 





White mouse 


In traperitoneal 







Pak and Read 

White rat 





Guinea pig < 

1 Hydrochloride 



Amatsu and 

White rabbit 


Subcu taneou fl 



Pak and Read 

Gray rabbit < 




Pak and Read 

Cat | 
Dog < 





Pak and Read 
Pak and Read 

* Total dose. 






route of administration is 70 to 75 mgm. per kilogram. It is interest- 
ing to note the great deviation of the M.L.D. in mice obtained by 
Kreitmair from those reported by Fujii and by Rowe. The difference 
by subcutaneous injection is fully 100 per cent or more. One wonders 
if these three workers experimented on the same species of animals. 
The variations in the results, not more than 10 to 20 per cent among 
other investigators, should not be considered significant if one bears 
in mind the errors in the determination of toxicity. Such errors have 
been critically analyzed by Trevan (Proc. Roy. Soc., 1927, B, ci, 483) 
and by Burn (Methods of Biological Assay, London, 1928). 

b. Toxic symptomatology. Miura (1887) briefly described the toxic 
signs in animals with lethal doses of ephedrine. He observed general 
depression, mydriasis, stoppage of the respiration and diastolic stand- 
still of the heart in frogs. The signs of poisoning in mice, rabbits 
and dogs, as stated by him, are mydriasis, elevation of temperature, 
acceleration of the pulse and respiratory rates, fall of blood pressure, 
clonic convulsions and death due to cardiac and respiratory failure. 
Amatsu and Kubota (1913) reported about the same results. More 
detailed investigations were carried out by Chen on frogs, rats, guinea 
pigs, rabbits, cats and dogs. In his experience, cardiac collapse 
occurs sooner than respiratory failure. Animals poisoned by sub- 
lethal doses of ephedrine recover without complications. A full 
account of poisoning symptoms in frogs, mice, guinea pigs, rabbits and 
cats is also given by Kreitmair. 

The picture in the squid, described by Nadler, may be worth men- 
tioning. Ten milligrams of ephedrine given subcutaneously fre- 
quently cause gangrene and necrosis at the site of injection, leaving 
the muscles of the mantle exposed. The animal may, however, live 
for hours. Oral administration and injection into the circulation via 
the heart, in 5 to 10 mgm. dosage, produce a dark coloration. In 
these cases the arms are extended and limp, and on stimulation they 
go into a series of tonic contractions. The respiratory movements 
are faster and heavier, gradually become slower and labored, and death 

c. Repeated administration. In a series of rabbits Chen gave daily 
doses of ephedrine for several weeks intravenously, intramuscularly 
and orally and reported that the drug produces no observable toxic 


effects. These animals gained in weight as steadily as the controls. 
Upon sacrifice, there were no gross or microscopic lesions in the visceral 
organs. No tolerance is developed to the mydriatic or pressor action 
of ephedrine by repeated administration, nor is there any change in the 
dose required to cause death. Similar results were obtained in rats. 
This work has recently been verified by Doty. 


1. Methods of Administration and Dosage 

For systemic effects, ephedrine can be given by mouth, by sub- 
cutaneous or intramuscular injection, and only exceptionally by 
intravenous administration. On occasion, the drug may be used per 
rectum, as shown by Thomas and by Hess. For local application to 
the nasal mucous membrane, concentrations varying from 1 to 5 
per cent can be used. It may be in the form of a solution, pure or 
mixed with other aromatic ingredients, a jelly or a snuff. As a 
mydriatic, ephedrine is used in 5 to 10 per cent aqueous solutions. 

As regards the dosage for internal administration, this is governed 
entirely by the development of untoward symptoms. A small dose 
for one individual may be a large one for another. From the 
experience of early investigators, a single dose may be 50 to 100 mgm. 
for an average adult. Hess advocates the use of 1 to 2 mgm. 
per kilogram of body weight. This dose appears to be slightly too 
large, especially for ambulatory patients, judging from the frequent 
occurrence of side reactions. It has now been reduced to 25 to 50 
mgm., and may be repeated as needed. It can be given three or four 
times a day. 

In children from 2 to 14 years of age, Munns and Aldrich use 12 to 
50 mgm. of ephedrine by mouth. Anderson and Homan employ 
J grain (15 mgm.) for those over 1 year of age and \ grain (7.5 mgm.) 
for those under 1 year, the drug being given in water solution. Stewart 
prescribes $ grain (10 mgm.) in children from 1 to 5 years, J to J grain 
(15 to 30 mgm.) from 5 to 6 years, $ grain (7.5 mgm.) from 6 to 12 
months, and -fa grain (5 mgm.) under 6 months of age. Such doses 
are given with 20 minims of glycerine and enough chloroform water 
to make a dram (4 cc.). 


2. Side effects 

The untoward symptoms of ephedrine, given orally, subcutaneously 
or intramuscularly, have been recorded by T. G. Miller, Rowntree 
and Brown, Gaarde and Maytum, Pollak and Robitschek, MacDer- 
mott, Hollingsworth, Thomas, Balyeat, BergerandEbster, Althausen 
and Schumacher, Wu and Read, Anderson and Homan, Kesten, 
Middleton and Chen, Wilmer, Gay and Herman, Bloedorn and 
Dickens, Boston, Long, S6gard, Chopra, Dikshit and Pillai, Higgins, 
and Stewart hi connection with their clinical investigations. The 
development of such symptoms and signs depends upon the dosage but 
more upon the stability of the nervous system, as emphasized by 
Pollak and Rabitschek. Similarly, Gaarde and Maytum state that 
the occurrence of the nervous smptoms bears a distinct relationship 
to a neurotic tendency and the daily activity of the individual. The 
same therapeutic dose, therefore, may produce only desirable effects 
in one patient, and equally beneficial results but with some discomfort, 
hi another. Meals sometimes aggravate the symptoms (Middleton 
and Chen) . It is the best plan to test out the sensitivity of the patient 
with small doses, say 10 mgm., and establish the maximal tolerated 
dose. It is only by experience and judgment that these side reactions 
can be reduced to a minimum. 

Subjectively, the common symptoms are palpitations, trembling, 
weakness, sweating, feeling of warmth, chilly sensation, nausea, and 
vomiting, while those of less frequent and rare occurrence are nervous- 
ness, headache, insomnia, dyspnea, a tired feeling, thirst, drowsiness, 
precordial pain, feeling of distress in the precordium, flushing of the 
skin, tingling and numbness of the extremities, anorexia, constipation, 
quivering feeling, faintness and diuresis. Boston makes a special 
report of difficulty in urination in 6 cases he observed. Berger and 
Ebster give an account of a neurotic patient who had colic, followed 
by diarrhea and anorexia, after the use of ephedrine, and of still 
another who had such an increase of libido that he called ephedrine an 
aphrodisiac. Higgins reports a case of chronic ephedrine poisoning 
which simulated hyperthyroidism. 

Objectively, the common signs are diaphoresis, tremor, extrasystoles 
and tonal arrhythmia, while those of less frequent or rare occurrence 
are tachycardia, restlessness, mydriasis, albuminuria, appearance of 


red blood corpuscles and casts in the urine, and decompensation in 
organic cardiac disorders. Anderson and Homan observed abdominal 
distension, pain and discomfort, discharge from the nose and apparent 
suppression of urine. T. G. Miller recorded a case of myocardial 
degeneration in which ephedrine caused pulsus alternans. Four out 
of 11 cases in the series of Middleton and Chen showed after ephedrine 
extrasystoles of ventricular or auricular origin, as shown by electro- 
cardiography. Another case developed a paroxysm of tachycardia 
which lasted for a few minutes. Bloedorn and Dickens describe a 
case of cardiac asthma, diagnosed as bronchial asthma, which resulted 
in cardiac embarrassment, including pulsus alternans, marked tachy- 
cardia and cardiac decompensation, following ephedrine therapy. 
Such dangerous effects, however, do not appear to occur very fre- 
quently, for in the series of Hess and of Gay and Herman there were 
several patients with myocardial insufficiency but none experienced 
any harmful effects. Pennetti observed, by means of electrocardio- 
grams, that ephedrine increased the frequency of pre-existing extra- 
systoles in 2 case's but produced no change in a case of A-V block of 
vagal origin. The block in the last case disappeared after the adminis- 
tration of atropine or epinephrine. 

All the side effects occur singly or in groups of but a few, become 
most pronounced when the systolic blood pressure is at its highest level, 
and disappear as the pressure returns to normal. Some of the sub- 
jective symptoms may be explained by the pharmacological action of 
the drug. For example, palpitation is due to circulatory changes, 
as borne out by objective observation, and the insomnia and tremors 
present in some cases are due to stimulation of the central nervous 
system. Leake, Loevenhart and Muehlberger attribute the headache 
under ephedrine to the changes in pressure in the arteries or veins 
within the skull. Occasionally, the untoward symptoms in some in- 
dividuals disappear on repeated administration of ephedrine, showing 
that these individuals become better accustomed to the drug. Alt- 
hausen and Schumacher mention two such cases and HoUingsworth 

Investigators seem to agree that the prolonged use of ephedrine 
does not have any cumulative harmful effects and does not result in 
habit formation. Middleton and Chen reported a case that received a 


total quantity of 10 grams of ephedrine sulphate in a period of 11 days 
but showed no detectable pathological changes. Withdrawal did not 
give that patient any discomfort or any craving for the drug. Wu 
and Read mentioned a case in which ephedrine therapy (40 to 60 
mgm. every 1 to 3 days) was continued for three years. Laboratory 
examinations did not show any ill effects. Thomas and Balyeat, 
and Collina also express the opinion that ephedrine is not a habit- 
forming drug. In 5 out of 51 cases of asthma and hay fever, Althau- 
sen and Schumacher noted a considerable diminution of action in the 
relief of attacks, showing the increase in tolerance by repeated admin- 
istration. It should also be borne in mind that the attacks may 
not have been of equal severity and that severe cases are unfavor- 
able for the action of ephedrine. 

Contraindications are but few. In all cardiac disorders, especially 
with signs of decompensation, ephedrine should be used with caution. 
Slgard mentioned angina and hypertension as contraindications of the 
use of ephedrine. However, recent work on spinal anesthesia shows 
that it is permissible to use ephedrine in hypertension cases. Care 
should also be taken in cases where there is a labile vagosympathetic 
equHibrium, although there is not the same extent of hypersensitive- 
ness to ephedrine as to epinephrine in Graves 3 disease (Cs6pai and 
Fernbach). In late acute circulatory collapse, it is best not to give 
ephedrine, since it may be a dangerous procedure, as shown by 
Blalock hi experimental annuals. 

Pitkin mentions two fatalities in spinal anesthesia which were 
attributed to 50 mgm. of ephedrine, but his own toxicological studies 
do not seem to support this statement. Sise knows of two similar 
cases, not of his own; each patient was in very poor general condition, 
received repeated doses of ephedrine, totaling about 150 mgm., be- 
came cyanotic, fibrillated and, although the pressure was at or above 
normal, died hi about 12 hours. In experimental animals, however, 
death never occurs if the blood pressure is at its normal level. 


1. In asthma 

Following the publication of T. G. Miller, who first employed 
ephedrine in the treatment of bronchial asthma, many other investi- 


gators have made similar reports concerning their experience with the 
drug. It appears to be generally agreed now that ephedrine is a good 
palliative remedy in the treatment of bronchial asthma. Its action is 
weaker than that of epinephrine, and it is therefore only occasionally 
efficacious in severe attacks of asthma. In mild and moderate cases 
it may prevent the attack if it is given several hours beforehand, abort 
the attack if it is administered during the prodromal period and some- 
times stop the attack when it is used while the attack is in progress. 
Its prophylactic action seems to be better than its antispasmodic 
property. This is well illustrated by the work of Vallery-Radot and 
Blamoutier, who showed that ephedrine was effective in 16 (69 per 
cent) out of 23 cases when given prophylactically but in only 17 
(43 per cent) out of 39 cases when given during the attack. Leopold 
and Miller show that the best results are obtained in allergic and reflex 
nasal cases, and comparativtely less satisfactory results are obtained in 
the infectious type. Similarly, Gay an4 Herman note that the relief 
from an asthmatic attack is most quickly obtained in patients whose 
symptoms are due to a specific foreign protein, such as pollens, animal 
emanations, orris root, feathers, with or without secondary bronchitis. 
According to Thomas, a field for the use of ephedrine appears to lie in 
its employment as often as necessary to prevent the occurrence of 
paroxysms in asthmatic patients who are awaiting the completion of 
skin testSj courses of vaccine administration, rhinological treatment, 
radiotherapy or other methods from which more permanent benefit 
is hoped for. This author adds, however, that patients who are about 
to undergo sensitization tests should be cautioned not to seek relief in 
ephedrine within a period of 12 hours before such tests are to be made ; 
for the drug, like epinephrine, temporarily prevents the appearance 
of positive reactions to specific tests for sensitiveness. 

When desirable effects occur, ephedrine has certain advantages over 
epinephrine from the therapeutical point of view. In the first place, 
it can be given by mouth ; secondly, it can be employed as a preventive ; 
thirdly, it has a more prolonged action, although its onset is not so 
prompt ; and fourthly, it produces less side reactions. Some individuals 
who are unable to take epinephrine are fortunately able to use ephe- 
drine without untoward symptoms. In other words, a reaction from 
epinephrine does not indicate that ephedrine likewise will have a 




Results of ephedrine therapy in the treatment of asthma 

T.G. Miller (1925). 
T. G. Miller (1926) . 

Leopold and T. G. Miller 

Thomas (1926) . 
Thomas (1927) . 


Pollak and Ro"bitschek 

Hess . 


Kammerer and Dorrer. . . 
Middleton and Chen . . 

Piness and Miller .... 
Althausen and Schumacher. 


Wu and Read. 

Bibb . . 

Rudolf and Graham 

Collina . . . 





Over 300 








(Ward) 11 

(Ambulatory) 90 


Over 100 

(Severe) 2 



Benefit in 6; none in 1 

Good results in 26, relief not 

marked in 4; no improvement 

in 6 

Complete relief in 33; partial 
relief in 17, no relief in 9 

Relief in 17 

Ephednne is a remarkably effi- 
cient drug 

Relief in most cases 

Ephedrine replaces epinephrine 

Very good in part, good in part; 
rarely insufficient success 

Marked improvement (observa- 
tion made on himself) 


Relief in 8; none in 1 

Relief in 9; improvement in 8; 
inconclusive in 8 

24 severe cases did not obtain 

Complete relief in 21; partial 
relief in 15 

Relief in 75; relief in severe 
attacks, 10 


9 responded well 


Perfect relief 

Ephednne is of considerable 
value in 65 per cent of the 

Ephedrine reduced epinephrine 
injections in one, but had no 
effect in the other 

Ephedrine has a marked effect 

Complete relief in 5, evident 
improvement in 5; temporary 
improvement in 2; no change 
in 3 

Prompt relief in every case 



Gay and Herman 

Vallery-Radot and Blamoutier 




Munns and Aldrich. 

Anderson and Homan. 

TABLE 3 Concluded 




(Children) 22 

(Children) 5 

Complete relief in 71; moderate 
relief in 21, no relief in 8 

In 23, ephedrine used prophy- 
lactically, produced benefit in 
16 but none in 7; in 39 ephe- 
drine given during the attack, 
gave relief to 17, but none to 

Complete relief in 9; partial in 2 

Total relief in mild cases 

Effective in relief and prevention 

Complete relief in 12; partial in 
4; none in 6 

Marked relief 

Relief in over half 

similar unpleasant effect. A combination of epinephrine and ephe- 
drine has been found efficacious by some and objectionable by others. 
On the whole, if the patient shows reactions to epinephrine alone, or 
to both epinephrine and ephedrine, the injection of epinephrine in the 
presence of ephedrine usually exaggerates the untoward symptoms 
(Althausen and Schumacher, and Haintz) . If the patient can tolerate 
both drugs well, there is no reason why epinephrine cannot be given 
in addition to ephedrine if the latter fails to act. 

Relief from ephedrine takes place in 20 to 30 minutes if it is given by 
mouth but in 10 to 15 minutes if it is administered intramuscularly or 
subcutaneously. The clinical improvement can sometimes be ob- 
served objectively. It consists in diminution of cyanosis, increase 
of vital capacity, decrease of rales, gradual disappearance of orthopnea, 
and euphoria of the patient. Subjectively, the patient usually volun- 
teers the information that he can breathe better and feels relieved. 
The relief may be followed by coughing and expectoration (Heller). 
Individuals who suffer regularly from daily or nightly paroxysms may 
remain asthma-free for long periods of time by taking the drug once, 
twice or three times every 24 hours. They can resume their daily 
activities and pass comfortable nights. Withdrawal of the ephedrine 
results in recurrence of asthmatic symptoms. Other persons are not 


so fortunate, for the by-effects, occasionally met with, render its use 
impracticable even though it relieves the bronchospasm. 

In children afflicted with asthma the same beneficial results have 
been obtained with the proper doses of ephedrine, as reported by 
Munns and Aldrich and by Anderson and Homan. 

The results of various workers, not only in this country but in 
various parts of the world, are summarized in table 3. It will be seen 
that beneficial results have been obtained in the majority of cases by 
each physician. It is futile to compare the percentage of improve- 
ment in different series since the essential factor is not the patient 
or the drug but the severity of the asthmatic attack. 

2. In hay fever 

Gaarde and Maytum in 1926 reported their first series of 26 cases 
of autumnad hay fever which were treated by the oral administration 
of ephedrine. Thirteen of these patients obtained complete or almost 
complete relief from symptoms by taking 60 mgm. doses 2 to 3 times 
every 24 hours. The relief lasts 3 to 7 hours after each dose. Ex- 
cessive nasal secretions stop, ocular symptoms disappear, and in every 
way the patients are entirely comfortable. In 5 cases the result was 
fair and partial relief was obtained for 2 to 3 hours after each dose. 
In 8 cases the results were negative. In their next series, published 
in 1927, they made a comparison of the effects of oral administration 
with those of a 3 per cent nasal spray. In 24 patients who received 
ephedrine by mouth, 13 (54 per cent) were completely or almost com- 
pletelyrelieved for4hoursormore; 7 (29 per cent) werepartially relieved; 
and 4 (16 per cent) were not relieved or they were not able to tolerate 
the nervous symptoms. In a similar series of 25 cases which were 
given ephedrine by a spray, 7 (28 per cent) were markedly relieved for 
several hours; 12 (48 per cent) were partially relieved for several 
hours or completely relieved for less than an hour; and 6 (24 per cent) 
were not benefited. Ephedrine given in 3 per cent solution as a nasal 
spray, therefore, appears to be less efficacious and the relief is of shorter 
duration. However, the majority of patients feel that its use adds to 
their comfort. The best results are obtained when the spray is used 
early in the paroxysm. The effect of both the local and internal ad- 
ministration seems to depend on the severity of the paroxysms and 


the good results are obtained in the milder seizures. Untoward symp- 
toms, when they occur, are attributable to the neurotic temperament 
and nervous state of the patient. In analyzing their data of two suc- 
cessive seasons, Graarde and Maytum conclude that ephedrine should 
be given a definite place in the treatment of autumnal hay fever, and 
they emphasize the fact that when good effects are obtained they are 
temporary and symptomatic. Leopold and Miller observed complete 
temporary relief in 63 per cent of 11 cases and prefer the oral route for 
the administration of ephedrine. Encouraging results in the treatment 
of hay fever with the new drug are also noted by Thomas, Balyeat, 
Althausen and Schumacher, Wilkinson, and Ramirez. Piness and 
Miller observed relief in only 1 out of 5 cases when ephedrine was 
given by mouth, but in 18 out of 20 cases when the drug was used as a 
spray. These results show that local application is more efficacious 
than oral administration. 

3. In bronchitis and emphysema 

In 11 cases of senile emphysema, 1 with active and 6 with inactive 
pulmonary tuberculosis and all having hypotension, Saxl reports 
that ephedxine produced a striking improvement of the dyspnea in 8 
but had no effect in 3. The blood pressure rose 15 to 30 mm. Eg for 
several hours with 100 mgm. doses. According to him ephedrine has 
the advantage over atropine in that it does not cause dryness of the 
throat. These conclusions have been confirmed" by the study of a 
larger series of cases by himself. 

4. In whooping cough 

Anderson and Homan were the first to try out ephedrine therapy in 
pertussis. They noticed that the drug abolished the characteristic 
signs of whooping cough in 18 out of 20 children. In all instances in 
which improvement occurred, some cough remains but in mild form 
and of a type associated with acute upper respiratory infections. 
They believe that ephedrine is most useful during the second stage of 
the disease. In a series of 35 children suffering from pertussis Stewart 
observed that ephedrine relieves the coughing, the whooping and 
vomiting in mild and moderate cases. In severe cases there is no 
effect at all. He states, however, that the drug, combined with 


belladonna and ipecac, seems to have a beneficial effect. The progress 
of the infection is not in any way influenced. 

5. In spinal anesthesia 

The blood pressure-raising property of ephedrine appears to be most 
useful in spinal anesthesia. Rudolf and Graham studied 26 cases 
under spinal anesthesia, in the surgical and gynecological wards of a 
hospital, in which they administered ephedrine intravenously. Their 
results are striking, especially with reference to the elevation of the 
blood pressure. In their first few cases the blood pressure was allowed 
to drop until it had apparently reached its lowest level and then 50 to 
100 mgm. of the drug were given by vein. With but one exception 
there quickly resulted an extraordinary and prolonged rise in blood 
pressure, with a slower and stronger heart beat. This lasted for 1 to 
1 hours. In their later cases they used smaller doses and gave the 
ephedrine within 2 to 3 minutes after the anesthetic, so as to antic- 
ipate the fall rather than combat it after it had developed. This 
improved technique proved to be satisfactory and they had no case of 
drastic fall in blood pressure or of vomiting, which occurs frequently 
in spinal anesthesia. They also state that the drug can sometimes be 
given with advantage before the spinal anesthetic where the blood 
pressure is already too low. Ockerblad and Dillon have used ephe- 
drine in 50 to 100 mgm. dosage, subcutaneously or orally, in a series of 
250 cases and have been successful in restoring the right amount of 
arterial tension necessary for surgical operations and the well being of 
the patient. The fall in pressure must be anticipated if the best 
results are to be obtained with ephedrine. In other words, once the 
pressure falls as much as 50 per cent, the return to the normal level 
even under comparatively large doses of the drug is slow and uncer- 
tain. It is better to reinforce the vascular system with ephedrine 
before the actual administration of the spinal anesthetic, to have the 
blood pressure 20, 30 or more millimeters Hg above the normal for 
that individual. The drug is repeated if there is a tendency to fall. 
Chronic hypotension, which used to be a contraindication to spinal 
anesthesia, is no longer a valid objection. Ephedrine relieves any 
tendency toward retching and vomiting which, according to Ockerblad 
and Dillon, is due to the preliminary hypodermic injection of morphine 


and scopolamine. Pitkin uses 1 to 1.3 cc. of a solution containing 
1 per cent of novocaine and 3 per cent of ephedrine to make a wheal at 
the site of, and before, lumbar puncture. He is satisfied with the 
pressor action of ephedrine and performs operations below the dia- 
phragm. He states that the action of the drug can be relied on 
for 2 to 3 hours and has contributed much to the safety of spinal 
anesthesia. Pitkin and McCormack, and Cosgrove have tried the 
drug in obstetrics where spinal anesthesia may be indicated, as in low 
forceps extraction, episiotomy, perineorrhaphy, dilatation or incision 
of the cervix, podalic version, craniotomy and extraction, vaginal 
hysterectomy, etc. Ephedrine is used prophylactically as outlined 
by Pitkin. Holder gives ephedrine subcutaneously IS minutes before 
the administration of the spinal anesthetic and succeeds in keeping the 
systolic blood pressure at a constant level, although somewhat below 
the original. In 151 cases, approximately one-half received ephedrine 
(50 to 100 mgm.) and the average drop of blood pressure was 12.8 
mm. Hg. In the other half the average drop of pressure was 37.5 
mm. Hg. Wehrheim reports his experience in over 300 cases of spinal 
anesthesia with ephedrine (50 mgm.) injected subcutaneously 5 min- 
utes before the spinal tap. To show the benefit of this procedure, he 
states that the average drop in blood pressure in spinal anesthesia 
without ephedrine is 10 to 30 mm. Hg within 15 minutes, but the 
average drop in 30 consecutive medicated cases was nil. Sise con- 
siders the repeated injection of ephedrine unnecessary and sometimes 
dangerous if the blood pressure begins to drop in spite of the use of 
ephedrine. Other measures, such as saline infusions with small doses 
of epinephrine, should be resorted to. Other favorable reports of 
spinal anesthesia with ephedrine have been made by Babcock, Wallace, 
Jeck in kidney and ureter operations,' DeCourcy, Case who uses the 
drug subcutaneously immediately after the spinal injection, Gosse, 
Saklad, and Russell who injects ephedrine intramuscularly before the 
spinal puncture. 

6 . In hypotension 

The use of ephedrine in the treatment of chronic or subacute hypo- 
tension has, with some exceptions, not proved as promising as had been 
hoped for. It has been tried in Addison's disease. Chen and Schmidt 


mentioned a single case in which ephedrine seemed to have a good 
effect. T. G. Miller studied two cases of early Addison's disease and 
found a rise of blood pressure and increase of basal metabolic rate fol- 
lowing the administration of ephedrine, but both patients died from the 
disease. Rowntree and Brown treated 14 cases of Addison's disease 
and two of questionable Addison's disease with ephedrine. They also 
demonstrated a definite rise of blood pressure and increase of metabolic 
rate, but the rise was not accompanied by a marked feeling of well 
being, significant increase in strength or relief from the gastric symp- 
toms or circulatory asthenia. Only in one case of early Addison's 
disease excellent clinical results were obtained. The feeling of weak- 
ness and exhaustion disappeared and the patient felt buoyant, strong 
and refreshed. 

T. G. Miller tried ephedrine in a number of cases with essential or 
chronic hypotension and observed that in some of them it produced 
a temporary elevation of pressure, lasting from 3 to 6 hours after each 
dose by mouth. The response in pressure increase was not as striking 
as in certain other types of cases, and' sometimes a dose of 50 mgm. 
had no effect whatever on the hypotension, yet most of the patients 
expressed themselves as feeling stronger and more energetic under its 
influence. Rowntree and Brown administered ephedrine in 9 cases of 
nervous exhaustion and hypotension. Aside from the rise of blood 
pressure for 3-6 hours and some increase of the basal metabolic 
rate, no other evidence of clinical improvement was observed objec- 
tively, although some of the patients were convinced that they felt 
somewhat stronger. Pollak and Robitschek mentioned a case of 
pneumonia in which daily doses of ephedrine raised the blood pressure 
from a level below 100 mm. to 145 mm. Hg, although accompanied by 
some untoward symptoms. Hess reported a series of cases with hypo- 
tension, including pneumonia, bronchopneumonia, pulmonary tuber- 
culosis, cardiac insufficiency and vasomotor weakness. Repeated 
small doses of ephedrine produced favorable results . In the treatment 
of paresis with malarial fever, the drug can maintain the blood pres- 
sure at the normal level, as shown by three cases. He advocates the 
combination of ephedrine with atropine in the treatment of bronchial 
asthma and with digitalis or caffeine in cardiac insufficiency with low 
pressure and chronic bronchitis. Middleton and Chen studied three 


patients who had hypotension two with asthma and one without 
asthma with ephedrine at frequent intervals for a considerable length 
of time, in the hope of elevating their blood pressure and maintaining 
the higher pressure. The results in two were practically negative. 
The slight elevation in the third was probably due to the improvement 
of his asthmatic condition under ephedrine therapy. Wu and Read, 
on the other hand, state that they obtain very satisfactory results 
with ephedrine in cases of hypotension. Althausen and Shumacher 
determined the value of ephedrine in 7 patients with chronic hypo- 
tension. During an average period of 20 days the blood pressure was 
raised by daily doses of the drug and three patients felt stronger while 
four did not notice any change. Ghrist and Brown reported an 
interesting case of postural hypotension with syncope, in which ephe- 
drine raised and sustained the blood pressure and rendered the patient 
free from symptoms. He has been able to go back to work without 
further attacks by the daily use of the drug. These authors believe 
that ephedrine may exercise a specific alleviative effect on the disease. 

7. In shock 

In acute circulatory collapse it is still a question how much good 
ephedrine can do. The drug is not indicated in late stages of shock. 
Chen in dogs observed that ephedrine restores the blood pressure in 
hemorrhage and in experimental shock induced by histamine, peptone, 
anaphylaxis or surgical manipulation, and that it fails to act when the 
heart beat becomes impaired or respiration ceases, or the degree of 
shock is too extensive, or when the hemorrhage exceeds 25 per cent of 
the total blood volume. Blalock, also experimenting with dogs, con- 
cluded that in less severe cases of shock ephedrine works better than 
caffeine, strychnine, epinephrine and digitalis, but in severe cases it 
seems to hasten death. Chen and Schmidt investigated its effect in 
surgical shock in a single patient, with encouraging results. Miller 
reported real improvement in two cases in profound shock. In one of 
them an intravenous injection of 100 mgm. raised the blood pressure 
from practically zero to 65 mm. Hg, although the patient finally died of 
general peritonitis. Since then, he has tried the drug in a large num- 
ber of cases of shock and hemorrhage, usually without beneficial 
result, even though the drug was given intravenously (unpublished). 


Pollak and Robitschek recorded a case of acute alcoholic poisoning in 
which ephedrine caused a definite increase in blood pressure from an 
almost imperceptible pulse. Similarly, in a patient dying of post- 
operative peritonitis Rudolf and Graham administered 100 mgm. of 
ephedrine intravenously. The systolic blood pressure rose from an 
unrecordable level to 86 mm. Hg. within 2 minutes and later to 130 
mm. Hg. The good effects lasted for some 45 minutes and then the 
patient gradually sank and died some five hours later. Althausen and 
Schumacher reported two cases in a state of surgical shock in which 
ephedrine was given. One of them rapidly recovered and the other 
died. Both were given blood transfusions simultaneously. Waters 
(cited by Jackson) believes that the chances for a favorable result from 
the action of ephedrine are much increased if it is given in the early 
stages of traumatic or surgical shock. H. Schmidt advocates the use 
of ephedrine as a prophylactic measure against vascular shock in local 
anesthesia and surgical shock in major operations under chloroform, 
spinal or avertin anesthesia. The action usually lasts longer than the 

8. In Adams-Stokes' syndrome 

In a single case of complete heart block T. G. Miller gave a subcu- 
taneous injection of 100 mgm. of ephedrine : it caused an increase of the 
ventricular rate from 38 to 55 per minute, of the auricular rate from 
110 to 125 per minute, accompanied by a rise of blood pressure, as 
shown by electrocardiograms. The shape of the P-wave and the 
ventricular complexes was observed to alter from time to time. 
Hollingsworth was the first to report a case of Adams-Stokes' syndrome 
hi which the first dose of ephedrine (50 mgm.) by mouth stopped the 
attacks within 30 minutes. The latter did not recur in 36 hours. On 
taking the drug every morning the patient was completely freed from 
symptoms and was able to resume her household duties. After three 
weeks the drug was withheld but the attacks recurred in 48 hours. It 
was therefore resumed. Stecher reported a similar case of complete 
heart block with syncope and convulsions in which ephedrine gave 
complete relief. The patient was given 30 mgm. doses three times 
a day during the first week and 20 mgm. doses three times a day during 
the next two weeks. The drug was then discontinued and the patient 


had no further attacks for 10 weeks afterwards, during which time 
he was ambulatory. 

9. As a nasal astringent 

Dr. Alice H. Cook (cited by Fetterolf and Sponsler) was the first 
to use ephedrine locally in the nose and throat. She found that a 10 
per cent solution of ephedrine causes almost instant shrinkage of an 
engorged nasal mucous membrane and that the action is more rapid and 
complete than that of a 4 per cent solution of cocaine. This sub- 
ject was investigated more thoroughly by Fetterolf and Sponsler who 
used a 5 per cent solution in 17 patients and found it so effective 
that they described ephedrine as a drug which, for use in the nose, has 
all the advantages of epinephrine with perhaps none of its disadvant- 
ages. Following the application to the anterior part of the lower 
turbinate by means of a cotton brush, contraction begins in from a few 
seconds to one minute. The maximum is established in from l to 
5 minutes or in an average time, for their series, of 2f minutes. In 
spite of a small area of application the turbinate in every case contracts 
throughout its entire length. The general outline of the medial sur- 
face changes from convex to concave. Contraction is so complete 
and the mucosa becomes so thin and flat that it fits the bone as a glove 
fits the finger. The color is altered to a paler hue and assumes a 
gray tint at the maximum of the action. No white ischemia occurs, as 
is often seen with epinephrine. Relaxation begins in 2 hours and 35 
minutes and is complete in an average time of 3 hours and 17 minutes. 
There is no sign of irritation of the mucous membrane, such as sneezing, 
either on the same day or the following day. There is no secondary 
congestion, as with epinephrine. Similar favorable results have been 
obtained with weaker solutions (1 to 3 per cent) by Fiske, Proetz, and 
others. Kennon advocates the use of ephedrine in (1) acute nasal 
accessory sinus disease, (2) chronic nasal sinus disease where surgery 
is contraindicated and as an adjunct to surgery, and (3) chronic* 
accessory sinus disease in children where surgery should be used only 
for the removal of toxic foci. Merkel states that a 3 per cent solution 
of ephedrine is just as effective as a 5 per cent solution in rhinotherapy 
and the drug can be applied by (1) spraying, which is best for children, 
(2) topical application with cotton on a probe, and (3) introduction 


into the nose on cotton packs. Fifteen infants having definite evi- 
dence of ethmoiditis were treated by this author in the following man- 
ner: the nose was irrigated with a warm saline solution twice daily; 
half an hour after the irrigation a 2 per cent solution of ephedrine was 
sprayed on the nasal mucosa; and 5 minutes later 3 drops of a 5 per 
cent solution of argyrol were placed in the nostril. Twelve patients at 
least were benefited by such a regime. Ephedrine does not need to 
be in contact with the nasal mucosa for more than a few seconds. A 
pack left in situ for 3 minutes causes no more contraction than after 
a shorter time. Daily use over a period of 10 days shows no change 
in the rapidity or duration of the action. The drug brings about free 
ventilation and drainage for a period of 3 to 6 hours. Merkel also tried 
ephedrine in 3 cases of epistaxis and claimed to obtain good results. 
Reaves, employing a mixture of 1 per cent of ephedrine and 0.5 per cent 
of butyn, performs minor surgical operations on the nose. Gaarde 
and Maytum reported that ephedrine given orally produces a stop- 
page of excessive nasal secretions in cases of hay fever. They noticed 
sneezing in some patients. Leopold and Miller observed actual 
shrinkage of the nasal mucous membranes in similar cases by the same 
method of administration. In experimental animals (dogs) , a contrac- 
tion of the nasal mucosa and accessory sinuses following the intra- 
venous injection or local application of ephedrine has been demon- 
strated by Rudolf and Graham with Copeland's technique, by Jackson 
with his own device and by King and Pak with Tschalussow's nasal 

10. As a mydriatic 

The first ophthalmological work with ephedrine was done by Miura 
in 1887. He observed that a 6 to 7 per cent solution of ephedrine 
produces mydriasis in most people in from 40 to 60 minutes. The use 
of a 10 per cent solution in 18 patients did not cause a maximal dilata- 
tion of the pupil but produced sufficient dilatation for the visualization 
of the retina. During dilatation the light reflex is retained and the 
accommodation is not paralyzed. There is no increase in intra-ocular 
pressure, no irritation or inflammation follows its instillation and no ill 
effects result from prolonged use. One patient receiving three treat- 
ments daily for IS days showed no pathological changes. The dura- 


tion of mydriasis varies from 5 to 20 hours. Children and aged people 
are more susceptible than ydung adults. The diseased iris does not 
seem to respond well. De Vriesse published practically identical 
results in 1889. Inouje encountered a case in which the instillation of 
ephedrine precipitated an acute attack of glaucoma. Groenouw re- 
ported 100 cases he studied in which the following mixture was used: 
ephedrine hydrochloride, 1 gram; homatropine hydrochloride, 0.01 
gram; and water, 10 cc. Merck named this mixture Mydrin. The 
mydriasis with this combination begins in 8^ minutes, reaches its max- 
imum in 34 minutes and lasts for from 4 to 6 hours. The accommo- 
dation is not interfered with by this solution. In strong light the 
pupil contracts to 5.6 mm. in diameter. Similar favorable results 
have been reported by Suker, Snell, Cattaneo and Stephenson. Mar- 
moiton not long ago (1911) gave a re"sum6 of this work on ephedrine. 
All these authors advocated the use of ephedrine in the exploration 
of the fundus on account of the rapid action, absence of cycloplegia, 
short duration of mydriasis and harmlessness of the drug. Since the 
recent extensive study of ephedrine interest in its use in ophthalmology 
has been revived. Middleton and Chen observed that a 10 per cent 
solution of ephedrine, or the same concentration with the addition of 
0.1 per cent of homatropine or of 0.1 per cent of atropine, may be used 
locally as a mydriatic for routine ophthalmoscopic examinations. 
Chen and Poth found that ephedrine is an efficient mydriatic for 
Caucasians but is of little value in dilating the pupil of the Chinese 
and of negroes. The investigation was made both in diffuse daylight 
and under controlled illumination with accurate measurements. 
The same difference in mydriatic action in these three races was 
observed with cocaine and euphthalmine, which have hitherto been 
used indiscriminately in clinics. The question seems not to be 
entirely one of differentamounts of pigmentation, as rabbits of various 
colors respond almost equally to ephedrine applied to the conjunctiva! 
sac. Howard and Lee also reported that ephedrine is more effective 
as a mydriatic in individuals with light irides than in those with dark. 
Dittmann, on applying a 3 per cent solution on himself, experienced 
conjunctivitis, increased tension and blurring of vision. Schoenberg, 
on the other hand, concluded, from a study of several hundred patients, 
that a 1 to 3 per cent solution of ephedrine is a valuable drug to produce 


mydriasis for ophthalmoscopic examination. The same author ob- 
served that the effect of ephedrine on the human pupil is counteracted 
by pilocarpine within 5 to 10 minutes. Similarly, Muller, after 2^ 
years' experience, considers it as a useful agent for diagnostic purposes. 
This investigator administered ephedrine in several cases of chronic 
glaucoma and found no change in the intra-ocular pressure. Re- 
cently, Chen and Poth found that the dilated pupil in Caucasians 
under the influence of ephedrine is made more stable to light if a small 
amount of homatropine or euphthalmine is added. The mixtures 
have a short duration of action and some (but only little) influence 
upon the accommodation. As a result a better view of the eye ground 
is obtained without inconveniencing the patient by blurring of vision. 
The solutions are but little irritating. Some subjects experience a 
burning sensation which lasts for about 30 to 60 seconds. In uveitis 
and iritis, however, ephedrine, or its mixtures with other mydriatics, 
fails to dilate the pupil. 

11. As an antidote for narcotic drugs 

C. F. Schmidt observed in experimental animals that ephedrine 
possesses the power not only to increase the Oa supply of the brain by 
its pressor action but also to stimulate the respiratory center directly. 
He advocates the use of ephedrine and epinephrine in serious depres- 
sion or failure of the respiration, such as following morphine, in prefer- 
ence to the conventional respiratory stimulants, as caffeine, atropine, 
strychnine or camphor. Similarly, Kreitmair found that in rabbits 
and cats ephedrine, given intramuscularly or intravenously, not only 
restores the respiration after its paralysis by scopolamine but also 
raises the blood pressure. He suggests its clinical use in twilight sleep 
with scopolamine and morphine, or scopolamine and eucodal (dihy- 
droxycodeine hydrochloride). Subsequent reports seem to bear out 
his point. In psychiatry Guttmann used hypodermically ampules 
containing 1 mgm. of scopolamine and 25 mgm. of ephedrine in all cases 
of senile dementia, arteriosclerosis and 2 excited cardiac psychoses. 
During sleep these individuals had a quiet smooth breathing instead of 
snoring. The addition of ephedrine apparently does not affect the 
narcotic action of scopolamine. In surgery, Streissler reported 26 
cases in which he injected subcutaneously morphine and ampules 


containing 1 part of scopolamine and 25 parts of ephedrine to produce 
analgesia and anesthesia. These drugs are given in divided dosage. 
According to Streissler, 1\ hours before the operation the patient 
should be given 10 mgm. of morphine and 1 mgm. of scopolamine with 
25 mgm. of ephedrine. After 15 minutes 10 mgm. of morphine are 
given and 15 minutes later 1 mgm. of scopolamine with 25 mgm. of 
ephedrine is again injected. If sleep is not deep l hours before opera- 
tion, 0.5 to 1 mgm. with ephedrine, which is an extra dose, should be 
given. Finally, \ hour before operation, 10 mgm. of morphine, to- 
gether with 1 mgm. of scopolamine plus ephedrine are injected. With 
these medications the pain sensation disappears before tactile sensa- 
tion. There is no anxiety, fear or resistance on the part of the patient 
during induction of anesthesia. Many operations can be done under 
this form of analgesia and anesthesia, such as amputations of the 
breast, surgical treatment of the stomach or gall bladder, etc. In 
young vigorous persons ether may be given during the operation, but 
only as little as possible. The pulse rate is often unchanged but is 
usually accelerated after the operation. Respiration is slowed but 
not made stertorous. The blood pressure remains elevated for two 
hours after the operation. The patient wakes up hi 4 to 6 hours with 
complete amnesia and euphoria and without any struggling. Vomit- 
ing does not occur. The pain in the wound is not so severe. There 
were no postoperative complications that could be definitely attrib- 
uted to the drugs. Lubitz, working at the same clinic, reported 14 
more cases, using the same medication . Moro used this combination of 
scopolamine, ephedrine and morphine in 32 urological cases, and OstrCil 
for painless delivery. Similar results with the combination of eucodal, 
scopolamine and ephedrine in surgical operations have been reported 
by Dax and Weigand from 145 cases and by Wagner from several 
hundred cases. Merck has patented the scopol am i n e-ephedrine com- 
bination in England and Austria. 

12. In dermatology 

a. In urticaria. In view of the fact that ephedrine resembles epi- 
nephrine it has been tried out clinically in allergic conditions other 
than asthma and hay fever. T. G. Miller treated two cases of acute 
urticaria with ephedrine given by mouth and recorded beneficial 


results. Kesten made a careful study with ephedrine in a large series. 
She found that in 11 cases of chronic urticaria with angioneurotic 
oedema, 7 were cured, 2 improved and 2 unaffected. Several patients 
in this group had had urticaria almost continuously for years but be- 
came free from symptoms after taking the drug and remained so for 
some months after the medication had been discontinued. Results 
are less favorable in cases without oedema. Of 6 patients with chronic 
urticaria 2 had complete relief, 2 showed improvement and the remain- 
ing 2 no change, following the oral use of ephedrine. In 3 cases of 
papular urticaria, 2 of erythema multiforme and 2 of chronic eczema 
there was practically no relief except for lessened itching. Similarly, 
in a case of mild urticaria following the administration of serum but 
with no other symptoms of serum sickness, ephedrine produced no re- 
lief. Althausen and Schumacher reported that ephedrine gave 
prompt relief from itching and brought about disappearance of the 
lesions in a case of toxic erythema accompanied by pruritus, and 
effected improvement in 2 cases of urticaria but gave no relief in 5 
other cases of urticaria and 3 cases of angioneurotic oedema. Encour- 
aging results were obtained by Thomas in a few cases, and by Munns 
and Aldrich in a case of urticaria; by Berger and Ebster in a case and 
by Wilkinson in 2 cases of chronic urticaria; by McPhedran in a case of 
angioneurotic oedema; and by Sgard in a case of painful and purulent 
polymorphous erythema. 

b. In dermatitis medicamentosa. Perutz recommends the use of 
ephedrine in anaphylactic reactions from turpentine. Stokes and 
Mclntyre studied 68 cases which showed reactions towards arsphena- 
mine injections. They found that in 57.5 per cent of them ephedrine 
relieved such symptoms as nausea, headache, vertigo, dizziness, urti- 
caria, pruritus, pain, choking, coughing and repeated nitritoid crises. 
Besides, ephedrine reduced the fall of blood pressure from 28 to 6 
mm. Hg. 

c. In kprosy. The fact that epinephrine relieves the nerve pains 
of lepers led Muir and Chatterji to use ephedrine for this purpose in 
13 cases. They found that ephedrine does not interfere with the 
simultaneous use of potassium iodide, and its action lasts for 12 to 24 
hours. In their opinion, the beneficial effect is probably due to con- 
traction of the arterioles of the nerve trunks, thereby relieving their 


vascular engorgement. They admit that in certain cases ephedrine 
does not give relief. Cochrane and Mittra reported 10 cases of leprosy 
in which the lepra reactions, such as nerve pain, joint pain, swelling and 
other manifestations, were controlled by ephedrine. They consider it 
an extremely useful drug in relieving the distressing symptoms of 
lepra reactions. The relief is usually complete. Ephedrine has no 
action on the temperature, nor does it reduce the eruptions which 
appear during reactions in skin cases. According to these authors, the 
lepra reactions are allergic manifestations and ephedrine like epi- 
nephrine, is able to alleviate allergic conditions. 

13. In dysmenorrhea 

Assuming that dysmenorrhea is due to local or general increase 
of parasympathetic activity, Lang used ephedrine in 30 cases of 
essential dysmenorrhea. There was not only complete freedom from 
or diminution of pain, but also diminution of menstrual flow by one- 
half to one-third. Ephedrine was given as soon as pain appeared, 
usually 2 to 3 times a day. One patient experienced pain and a feeling 
of cold in the legs. Palpitation and tremor were observed in other 
cases. In one patient, repeated curettage did not produce any effect, 
but the use of ephedrine actually yielded good results. 


1. Synthetic or dl-ephedrine 

No sooner was the natural or /-ephedrine introduced to medical 
use than the synthetic or <#-ephedrine became a subject of study. It 
is optically inactive and is marketed by Merck under the name of 
Ephetonin. Kreitmair showed that qualitatively there is no difference 
between the action of natural and synthetic ephedrines. Thus, 
it has a prolonged pressor action, antispasmodic action, detoxifying 
action against scopolamine or morphine, oxytocic action and effec- 
tiveness by mouth. His results are in general confirmed by Chen and 
by Pak and Read, although the last two authors believe that the 
synthetic product is less sympathomimetic than the natural. Coelho 
in chloralosed dogs observed with electrocardiograms the appearance of 


extrasystoles, changes in Q.R.S. and alteration in T waves, block, and 
finally ventricular fibrillation, with various doses of synthetic ephe- 
drine. As with the natural drug, Chen found relaxation of the isolated 
rabbit's intestine, hyperglycemia in rabbits, mydriatic action in ani- 
mals and in men, contraction of the nasal mucous membrane and acces- 
sory sinuses and a decrease followed by an increase of the kidney 
volume, with synthetic ephedrine. He also observed that there is a 
diminution or loss of pressor action if it is injected intravenously after 
a previous dose of itself or of natural ephedrine. 

In men, Hess, Petow and Wittkower, Saxl, Berger, Ebster and Heuer, 
and Nardelli reported a rise of systolic blood pressure by oral or rectal 
administration or subcutaneous injection of synthetic ephedrine. 
Berger, Ebster and Heuer, and Nardelli noted a primary leucopenia 
and secondary leucocytosis following the subcutaneous injection of 
synthetic ephedrine. Lublin showed that the synthetic product, when 
given by mouth, like the natural, produces hyperglycemia and inhibits 
the conversion of carbohydrates into fat. Cannavd obtained similar 
results. Euler and Liljestrand showed that synthetic ephedrine in 
men increases the 62 consumption and the minute cardiac output. 
Synthetic ephedrine delays the emptying time of the stomach and 
decreases the gastric acidity, as reported by Takacs. Fonseca and 
Trincao state that oral ad-ministration diminishes but subcutaneous 
injection increases the gastric acidity. 

Quantitatively, Kreitmair in his preliminary communication con- 
cluded that there was no difference between the natural and synthetic 
ephedrines. Hess shared the same opinion for men by oral or rectal 
administration. Petow and Wittkower, Saxl, and Berger, Ebster and 
Heuer, on the other hand, seem to agree that synthetic ephedrine has a 
weaker pressor action in men. Chen in 9 subjects found that the 
changes in blood pressure by the oral use of synthetic ephedrine are 
much less uniform than by that of natural ephedrine. Compared in- 
directly in pithed cats against epinephrine, the average ratio, as found 
by Chen, of the intensity of pressor action of synthetic ephedrine to 
that of natural ephedrine with optimal doses is 1:1.33. Curtis, 
using the same method, determined the ratio to be about 1:2. Schau- 
mann, and Launoy and Nicolle arrived at the same conclusion. Pak 
and Read, making direct comparisons in anesthetized dogs, gave the 


ratio of synthetic to natural ephedrine as 0.7:1 (or 1 : 1.43), which is 
close to the one obtained by Chen. A quantitative difference can 
also be shown in their mydriatic action. Under controlled illumina- 
tion and with accurate measurements, Chen determined in Caucasians 
the average ratio of the mydriatic action of synthetic ephedrine to that 
of natural ephedrine to be 1 ; 1 .29. Regarding the toadcity, Kreitmair 
found it to be the same in mice either by intravenous injection or by 
oral administration. Chen recorded that synthetic and natural ephe- 
drines, in the form of the hydrochlorides, given intravenously, both 
have a M.L.D. of 60 mgm. per kilogram in white rabbits. Pak and 
Read state that synthetic ephedrine is less toxic than natural ephedrine 
in frogs, rats, rabbits and dogs ; the reverse is true for hamsters. King 
and Pak studied in anesthetized dogs the ratio of the shrinkage of the 
nasal mucous membrane produced by natural and synthetic ephe- 
drines, respectively, and determined it to be 1 :0.8. 

Clinically, synthetic ephedrine has been tried wherever natural 
ephedrine is indicated. Petow and Wittkower treated 20 cases of 
bronchial asthma by oral use of synthetic ephedrine. Their results 
showed that in 12 cases the synthetic product rendered daily injections 
of epinephrine and asthmolysin unnecessary, in 5 it effected transient 
improvement without preventing severe attacks, but in the remaining 
three there was no response to the drug. Fischer treated 1 1 asthmat- 
ics with synthetic ephedrine and recorded improvement in 10. Ber- 
ger and Ebster in an elaborate investigation recorded unquestionable 
benefit from synthetic ephedrine in 10 cases of asthma and less signifi- 
cant results in 2 severe cases of the same ailment. Neustadt studied 
22 cases of bronchial asthma with synthetic ephedrine, and obtained 
good results in 16. SSgard treated 70 cases of asthma with the same 
drug and reported relief in 60 per cent, temporary or irregular improve- 
ment in 30 per cent, but no effect in 10 per cent. Gay and Herman 
(cited by Chen) used synthetic ephedrine in 16 cases of bronchial 
asthma, recorded relief in 7, questionable relief in 1, and no relief in 8. 
Favorable results in the treatment of asthma with the synthetic com- 
pound have also been reported by Jankowski, Beck, Guttmann, and 
Hamming. The majority of these investigators appear to agree that 
synthetic ephedrine is useful, like the natural product, in the preven- 
tion and arrest of mild and moderate attacks of asthma but less promis- 


ing in severe cases, and that it has a weaker action but produces less 
untoward symptoms than natural ephedrine . The dosage of synthetic 
ephedrine varies according to individual tolerance, but the average 
dose lies between 25 and 150 mgm. per os. 

Saxl treated 11 cases of emphysema with synthetic ephedrine, and 
reported success in 8 but no effect in 3. Similar improvement was 
observed by Berger and Ebster in 3 cases of chronic bronchitis with 
emphysema, chronic bronchitis and bronchitis associated with pul- 
monary tuberculosis. In hay fever Berger and Ebster, Kreitmair and 
Nardelli advocated the oral use and local application of synthetic 
ephedrine. Berger and Ebster observed relief of headaches in one 
case of hemicrania with angioneurotic oedema, but no effect in a case of 
chronic urticaria. Improvement of symptoms was reported by Frankel 
in a severe case of urticaria, by Sack in 20 cases of eczema, and by 
Nardelli in three cases of alimentary urticaria and two cases of 
arsphenamine intolerance. Michalowsky was successful in relieving 
malaise from roentgenological treatment, Poppe in controlling the 
untoward symptoms of withdrawal of morphine in two addicts, and 
Parade and Voit in arresting the attacks in a single case of Adams- 
Stokes' syndrome. In practically every instance, synthetic ephedrine 
was given by mouth. For acute infectious rhinitis, Berger and Ebster 
used a 5 per cent solution of synthetic ephedrine as a spray. Slack 
(cited by Chen) found that in 4 cases of hypertrophied turbinates and 
3 cases of acute rhinitis, a topical application of the 5 per cent solution 
produces a marked contraction of the turbinates. In a few other 
cases of swollen turbinates, where natural and synthetic ephedrine 
were used side by side in the same individuals, he was unable to 
detect any significant difference between their constricting power. 
Frankel described a case of vasomotor rhinitis in an opera singer, with 
symptoms of sneezing, running of the eyes and dyspnea which were 
controlled by the oral administration of synthetic ephedrine. Sattle 
advocated the use of synthetic ephedrine in ophthalmology. Ac- 
cording to him, a solution containing 5 per cent of synthetic ephedrine 
and 0.3 per cent of homatropine produces good dilatation of the pupil. 

2. Pseudoephedrine 

The natural pseudoephedrine is dextro-rotatory and is obtained from 
several species of Ephedra, including the ones yielding natural or I- 


ephedrine. The mydriatic action of pseudoephedrine was first studied 
by De Vriesse (1889). He observed that a 10 to 12 per cent solution 
when applied locally to the eye of men produces, in from 30 to 35 min- 
utes, mydriasis which lasts from 6 to 9 hours. There are no secondary 
effects after a single instillation, nor after its prolonged use, and no 
changes in intra-ocular pressure. Giinsburg (1891) in an extensive 
study on animals and 120 patients presented evidence that the mydria- 
sis produced by pseudoephedrine is caused by sympathetic stimulation. 
Grahe (1895) observed a slight rise of blood pressure in curarized cats 
after subcutaneous injection of the drug, and depression, block, 
arrhythmia and stoppage of the frog's heart at diastole, following the 
administration of pseudoephedrine. Fujii (1925) made a compara- 
tive investigation of pseudoephedrine with ephedrine. He reported 
that pseudoephedrine has a weaker pressor action in rabbits and a 
weaker mydriatic action on the enucleated frog's eye. It dilates the 
blood vessels in small doses but constricts them in large concentra- 
tions, as shown by theperfusion of the frog's legs and the rabbit's ear. 
Similarly, it relaxes the isolated rabbit's small intestines in small 
concentrations but stimulates them in strong solutions. It contracts 
the isolated rabbit's uterus in all concentrations. On the basis of these 
data, Fujii concluded that pseudoephedrine, like ephedrine, stimulates 
the sympathetic nerve endings but, unlike ephedrine, acts on smooth 
muscles directly in small doses. The same view is held by Pak and 
Read and by Chopra, Dikshit and Pillai. Chen made a similar com- 
parative study, and reported that pseudoephedrine has a weaker pres- 
sor action in dogs and in men, and a weaker mydriatic action in men. 
Vasodilatation in frogs and toads was reported by Loo and Read. 
Upon perfusion of the toad's heart, pseudoephedrine in the concentra- 
tion of 1 : 20,000 causes a decrease in rate but an increase in amplitude. 
Larger concentrations (1 :200) produce cessation of cardiac activity, as 
shown by these workers. Pak and Read found that ergotoxine does 
not invert, but cocaine abolishes, the pressor action of pseudoephe- 
drine. Liljestrand observed that pseudoephedrine contracts the 
isolated guinea pig's uterus and human uterus and that it has a 
stimulating action on the fundus of the rabbit's urinary bladder 
but no effect on the trigone. 
Quantitatively, Chen, Wu and Henriksen recently compared indi- 


rectly in pithed cats the pressor action of pseudoephedrine and ephe- 
drine, and found the average ratio of the intensity to be 1 : 5.1 7; that 
is, ephedrine is about 5 times as strong as pseudoephedrine. Pak and 
Read, by direct comparison in anesthetized dogs, concluded that 
ephedrine is twice as strong as pseudoephedrine. Their method is 
subject to criticism, as shown by Pittenger. King and Pak compared 
the shrinkage of the nasal mucous membrane in anesthetized dogs with 
ephedrine and pseudoephedrine and found the ratio to be 1 : 0.38. The 
toxicity was compared by Fujii who found that pseudoephedrine is 
less toxic in frogs but more toxic in mice. In white rabbits the 
M.L.D. of pseudoephedrine hydrochloride is 75 mgm. and that of 
ephedrine hydrochloride is 60 mgm. per kilogram of body weight, as 
shown by Chen, Wu and Henriksen. Pak and Read reported that 
pseudoephedrine is less toxic than ephedrine in frogs, rats, rabbits 
and dogs; the reverse is true in hamsters. 

Clinically, Howard and Lee tried out a 10 per cent solution of pseu- 
doephedrine in their eye clinic and concluded that it is an uncertain 
mydriatic and has no place in the treatment and examination of oph- 
thalmic diseases. Since its action is much weaker than that of either 
natural or synthetic ephedrine, it is not used in this branch of medicine, 
although it has been advocated by Chopra, Dikshit and Pillai on the 
basis of their experimental results. 

3. Other optical isomers of ephedrine 

Kreitmair showed that d-ephedrine is weaker in pressor action than 
/-ephedrine. This has been confirmed by Chen, Schaumann, and 
Launoy and Nicolle. Recently, Chen, Wu and Henriksen compared 
the pharmacological activity of the six optical isomers of ephedrine, 
courteously supplied by E. Merck of Darmstadt and Merck and Co., 
Rahway, N. J. The results are summarized in table 4. It will be 
seen that the mydriatic action of /-ephedrine and d-pseudoephedrine is 
greater than that of d-ephedrine and /-pseudoephedrine, respectively. 
When indirectly compared for pressor action in pithed cats with epi- 
nephrine, /-ephedrine is found to be about 3 times as strong as d- 
ephedrine, and (/-pseudoephedrine 7 times as strong as /-pseudoephe- 
drine. /-Ephedrine, the strongest isomer, is 35 times as powerful as 
/-pseudoephedrine, the weakest isomer of the six. When given by 



mouth to men in the same quantity, d-ephedrine and /-pseudoephedrine 
do not appear to raise the systolic blood pressure while the other four 
isomers do. Of the two sets of isomers ^-ephedrine and J-pseudo- 
ephedrine have the least toxicity. 

Pharmacological activity of the optical isomers of ephedrine 









26 40 


11 90 

6 80 






fflffli. jr kgm. 

4. Compounds related to ephedrine 

It has been shown that jS-phenylethylamine, CaH B - CH S - CH a -NH s , 
has a stronger pressor action than ephedrine (Chen, Alles) but is useless 
when given by mouth. The M.L.D. of the hydrochloride of 0- 
phenylethylamine in white rabbits, given subcutaneously, is 300 mgm. 
per kilogram of body weight. 

Phenylethanolamine, CBHs-CHOH-CHj-NHa, was first synthe- 
sized by Kolshorn (Ber. deut. chem. Gesell., 1904, xxxvii, 2474), 
later by Rosenmund (Ber. deut. chem. Gesell., 1913, xlvi, 1034), 
and Mannich and Thiele (Arch. Pharm., 1915, ccliii, 181), and is cov- 
ered by two German patents (D. R. P. 193, 631 and D. R. P. 244,321). 
The pressor action of this compound was described by Barger and 
Dale (Jour. Phys., 1910-11, xli, 19) and by Hirose. Alles recently 
found that it has a blood pressure effect in rabbits that is initially 
greater than and finally comparable with that of ephedrine, and a lower 
toxicity in guinea pigs by subcutaneous injection. The same author 
states that its tozicity is higher than that of ephedrine in rabbits by 
intravenous injection, while Chen, Wu and Henriksen reported the 
reverse in white rabbits. Tainter believes that the action of phenyl- 
ethanolamine is on the smooth muscles directly. Miller and Piness 
showed that this compound does not raise the blood pressure in men 


when taken by mouth and is useless in the treatment of asthma, but 
its activity on the congested nasal mucous membrane is in every 
respect comparable to that of ephedrine. Their results are in general 
confirmed by Chen, Wu and Henriksen. 

Nor-ephedrine, CeHs-CHOH-CHCHs-NHz, was obtained in a 
racemic form by Rabe and Hallensleben (Ber. deut. chem. Gesell., 
1910, xliii, 2622), Calliess, Nagai, and Eberhard (Arch. Phann., 1917, 
cclv, 140). Nagai patented his product under the name of Mydria- 
tine in the United States (U. S. Pat. 1,356,877) and in Japan (Jap Pat. 
27,056). Miura found that this compound (mydriatine) has a strong 
mydriatic action in men. The pupil begins to dilate in 20 to 30 min- 
utes and the mydriasis lasts for 24 to 36 hours. The accommodation 
is not unpaired. Hirose first observed its pressor action in animals. 
Amatsu and Kubota concluded that its action is quantitatively the 
same as that of ephedrine. Their data show that the M.L.D of 
mydriatine sulphate, given subcutaneously, is 0.4r-0.5 mgm. per gram 
in frogs, and 400 to 500 mgm. per kilogram in rabbits. Chen, Wu and 
Henriksen conclude from their study of ephedrine homologs and 
isomers that primary amines are more powerful than their correspond- 
ing methylated derivatives, and predicted that nor-ephedrine would 
be stronger than J/-ephedrine. This has been found to be true. The 
compound also raises the systolic blood pressure in men when given 
by mouth in 50 mgm. dosage. Its M.L.D. intravenously in albino 
rabbits is approximately 70 mgm. per kilogram of body weight. 
Kanao succeeded in resolving the racemic mixtures of nor-ephedrine 
into six optical isomers. According to Hirose (cited by Kanao), the 
order of activity of these optical isomers is as follows: 

Nor-^-pseudoephedrine > nor-dJ-ephedrine = nor-J-ephedrine 
Nor-tZ-ephedrine < nor-/-eph.edrine 
Nor-d-pseudoephedrine > nor-/-pseudoephedrine < nor-/-ephedrine 

Nor-^pseudoephedrine also occurs in Ma Huang, as shown by Smith, 
and confirmed by Nagai and Kanao. Chen, Wu and Henriksen 
reported that nor-d-pseudoephedrine has a weaker action than /- or dl- 
ephedrine, but a stronger action than ^-pseudoephedrine. It raises 
the systolic blood pressure in men when given by mouth. 
Tiffeneau, and TifFeneau, L6vy and Boyer synthesized three com- 


pounds of the general formula C^-CHOH-CHR-NHs, where R is 
ethyl, propyl or phenyl. The ethyl compound, C 6 H B -CHOH-- 
CHC a H B -NH 2 , called nor-homoephedrine, has a prolonged pressor 
action and a M.L.D. of 130 mgm. per kilogram in guinea pigs by 
subcutaneous injection, and inhibits the movements of the isolated 
dog's intestines, as shown by Tiffeneau. Its pressor action is weaker 
than that of ephedrine (Chen, Wu and Henriksen) . The propyl and 
phenyl derivatives have a depressor action, as reported by Tiffeneau, 
Levy and Boyer. 

Hyde, Browning and Adams synthesized a series of compounds of 
the general formula CflH B -CHOH- CHR'-NHR", where R' is hydro- 
gen, methyl, or -propyl, and R" is methyl, ethyl, -propyl, iso- 
propylj w-butyl or w-amyl. Most of these substances, including two 
prepared by Manske in which R' is methyl and R" is oxyethyl or 
benzyl were studied pharmacologically and compared with ephedrine 
by Chen, Wu and Henriksen . They are weaker than ephedrine . The 
general conclusion drawn by these workers was that with increase in 
the number of C-atoms in R' and R" the cardiac depressant action 
increases, the toxicity rises and the pressor action becomes a depressor 
action when R 7 or R" is equal to a propyl or higher alkyl group. 

ELanao prepared a similar series of compounds of the general formula 
C fl H B -CHOH-CHCH 3 -NHR, where R is ethyl, wo-amyl, heptyl, 
benzyl, 0-hydroxybenzyl, 0-vanillyl, vanillyl, piperonyl, w,-dihy- 
droxybenzyl, furfuryl or citryl. He states that the hydrochloride of 
the citryl derivative has a strong local anesthetic action. 

/-Methylephedrine, a tertiary amine isolated from Ma Huang by 
Smith, was proved to be much less active than ephedrine, a secondary 
amine, by Chen, Wu and Henriksen. The same conclusion was 
reached by Curtis with a series of tertiary amines related to ephedrine 
of the general formula CeHe-CHOH-CHCHa-NR'R'', where R' is 
methyl or ethyl, and R" is methyl, ethyl, oxyethyl, -propyl, iso- 
propyl or butyl. Some of these compounds, however, produce dilata- 
tion of the bronchi equal to that of ephedrine. The tertiary amine of 
the formula C fl H 6 -CHOH-CHC2HB-N(C 4 H 8 ) 2 , prepared by Hyde, 
Browning and Adams, has a depressor action, as shown by Chen, 
Wu and Henriksen. 

Nagai synthesized the following two substances with the idea that 


they might possess the anesthetic property of cocaine and the styptic 
action of epinephrine: 


O CO-CeHs O-CO-CeHs 

Attocain A Allocain S 

His process has been patented in Canada (Can. Pat. 177,019), Japan 
(Jap. Pat. 32,476) and the United States (U. S. Pat. 1,399,312). 
Kubota studied allocain S and found it to have a local anesthetic 
property but that it produces a primary fall of blood pressure in 
animals. The substance causes local irritation and necrosis so that its 
clinical use does not seem justifiable. 

Beaufour prepared w-methoxymethylephedrine, CaH B -CHOH-CH- 
(CH 2 - OCHs) -N(CH 8 )2, and found it to have a local anesthetic action. 
Brauchli and Cloetta reported that diallylephedrine, C e H B -CH- 
(OC 3 H 6 ) CHCH 8 NCH 3 (C 8 H 6 ), has a depressor action. 

Emde and Runne synthesized a-isoephedrine, C 6 H 5 -CHNHCH8-- 
CHOH-CHs. This compound is of interest because ephedrine for 
some time was considered to have the same structural formula. 

Dulire made synthetically several ethers of phenylpropanolamine, 
and studied their pharmacological action. 

Tyramine, H0<^ y>CH a CH 2 NH 2 , was proven to have a stronger 
pressor action than ephedrine but to be useless when given by mouth 
in men, as shown by Chen and Meek. Sympatol, H0<^ ^>CHOH- - 
CHNHCHa, which has recently been studied as a possible substitute 
for ephedrine by Ehrismann, Lasch, and Ehrismann and MalofF, has, 
on the other hand, a weaker pressor action than ephedrine, as observed 
by Chen, Wu and Henriksen. In view of the fact that the presence of 
an OH group at the ^-position usually intensifies the action, and the 
introduction of a methyl group on the a-C-atom from the N-atom 
prolongs the action, Chen, Wu and Henriksen suggested the synthesis 
of the compound H0<( )>CHOH CHCHs NH 2 , which was soon 
achieved by Hartung of Sharp and Dohme, Baltimore. It has in 
fact a prolonged and stronger pressor action, and is much less toxic, 
than either dl- or /-ephedrine in animals, but it has not been demon- 


strated that it produces systemic effects when given by mouth in men. 
Further study is needed here. 

Tiffeneau, Levy and Boyer synthesized ^-methoxy-norhomoephe- 
drine, CHsO^ ^>CHOH CHCaH s - NH a , and found it to possess a 
greater pressor action than nor-homoephedrine. Kohler prepared p- 
methoxyephedrine, CHaO^ ^>CHOH CHCHs NHCHs, and m- 

methoxy-^-oxyephedrine, HO<^ ^>CHOH CHCHj NHCH g , and 

found them to have no pressor action in rabbits. 

It is universally agreed that epinephrine H0<^ ]>CHOH CHj - 


NHCHs, has a strong but fleeting action, while ephedrine has a 
weaker but more prolonged action. The latter produces systemic 
effects when given by mouth. 0-Dihydroxyphenylethanolamine, 

HO<^ ^>CHOH CH a NH 8 , also has a stronger pressor action than 


ephedrine, as shown by Hirose. 

The compound HQ<( ^>CHOH CHCHg NH a , is mentioned in 


the German patent literature (D.R.P. 254,438, 256,750, 269,327) 
and has been studied pharmacologically by Tiffeneau (1920). The 
latter found that an Z-isomer resolved from its racemic mixture has 60 
to 75 per cent of the activity of /-epinephrine, but he did not study the 
duration of its action nor its absorption from the gastrointestinal tract. 
It seems desirable to compare its action with that of ephedrine. 

Kanao recently synthesized three series of compounds having the 
general formulae: 



where R 1 is methyl, ethyl or propyl, R a is methyl, heptyl, benzyl, 
piperonyl, diacetoxybenzyl, acetovanillyl or f urfuryl and R 8 is methyl, 


heptyl, benzyl or diacetoxybenzyl. The physiological activity of these 
substances has not been reported. 

From the above account it appears that there is no difficulty in 
synthesizing compounds related to ephedrine that are stronger 
pharmacologically in animals, especially by making primary amines 
and introducing 1 or 2 OH groups on the benzene ring. A prolonged 
action may also be imparted to them by introducing a methyl group 
on the a-C-atom from the N-atom. The absorbability from the 
gastrointestinal tract seems to be a peculiar feature of ephedrine, and 
this has made ephedrine particularly useful clinically because the drug 
can be given by mouth. Among the synthetic compounds, ^/-ephe- 
drine and <f/-norephedrine resemble natural ephedrine most closely 
and deserve a clinical trial. Some other compounds have a strong 
contracting power on the congested nasal mucous membrane in men, 
and a comparative study may yield profitable results. 


The following very brief summary is made from the practical point 
of view. 

1. Ephedrine is the chief active principle occurring in the Asiatic 
species of Ephedra. The other constituents that are present in 
the Chinese species are pseudoephedrine, nor-<2-pseudoephedrine, 
/-methylephedrine, and d-methylpseudoephedrine. 

2. Ephedrine is a stable compound. Its solutions are not decom- 
posed on exposure to air, light or heat, or by long standing. 

3. Ephedrine has been successfully synthesized by various methods. 

4. In mammals, ephedrine in suitable doses raises the blood pressure, 
increases cardiac activity, dilates the pupil, relieves broncho-spasm, 
contracts the uterus, more frequently inhibits than stimulates the 
gastrointestinal tract. These effects can be explained by the stimu- 
lation of the myoneural junctions of the sympathetic fibers. In cer- 
tain instances, there is an additional stimulation of the ganglia. It 
has been claimed by some investigators that it acts on the smooth 

5 . In animals, ephedrine does not have a marked effect on any of the 
body secretions. 


6. There is an increase in the formed elements of the blood and 
hyperglycemia, following the administration of a suitable quantity of 

7. Ephedrine increases slightly the basal metabolic rate and the 
oxygen consumption. 

8. Ephedrine may stimulate the central nervous system. 

9. Ephedrine is easily absorbed and has a low toxicity. 

10. In clinical use, ephedrine can be applied locally and given 
by mouth or by injection. Individuals who do not have a vago- 
sympathetic equilibrium may experience untoward symptoms. 

11. Ephedrine has been used with success in the treatment of bron- 
chial asthma, hay fever, whooping cough, bronchitis, postural hypo- 
tension and Adams-Stokes' syndrome, in combating the fall of blood 
pressure in spinal anesthesia, in antagonizing the action of narcotic 
drugs, in shrinking the congested nasal mucous membrane, and in 
dilating the pupil for ophthalmic examination. Its value in dermatol- 
ogy, shock and dysmenorrhea is promising. 

12. Compared with epinephrine, ephedrine has a less intense but 
more prolonged action. 

13. Of the many synthetic compounds, dZ-ephedrine and dl-noi- 
ephedrine deserve more extensive clinical trials. 

This review is intended to be as concise as possible. Naturally 
the authors could not discuss many valuable papers as fully as they 
desired. The literature consists of all those articles available on or 
before November 1, 1929. 


ABEL, J. J.: Chemistry in Relation to Biology and Medicine with Especial Reference to 

Insulin and other Hormones. Science, 1927, kvi, 307 and 377. 
AEBHA, Y.: (Jber die Einwirkung verschiedener Erregungsmittel der Grosshinrbde auf 

den chloralhydratschlaf. Arch, intern, de Pharmacodyn. et de Ther., 1913, 

xxiii, 453 
AIXES, G. A.. The Comparative Physiological Action of Phenylethanolamine. Jour. 

Pharm. Exp. Ther., 1927, sxrii, 121. 
ALTHATJSEN, T. L , AND SCHUMACHER, J. C. : Clinical Results with Ephedrin Therapy. 

Arch. Int. Med , 1927, ri, 851. 
AMATSTI, H. AND KUBOXA, S. : t)ber die pharmakologischen Wirkung des Ephedrins und 

Mydriatins Kyoto Igaku Zassi, 1913, x, 301 (original in Japanese) ; 1917, xiv, 

77 (original in Japanese), 5 (abstract in German). 


AMSLER, C. AND PICK, E. P. : tJber die strophanthinkontraktui der getrennten Kammer- 
half ten des Kaltbluterherzens. Pfltlgers Arch. Phys , 1920, clxxxiv, 62. 

ANDERSON, W. D. AND HOICAN, C. E., Jr: "Whooping Cough. Report of Twenty Cases 
Treated with Ephedrin Hydrochloride. Am Jour. Med. Sc., 1927, ckxiv, 738. 

AEBEH, E. A. N. AND PARKIN, J. : Studies on the Evolution of the Angiosperms. Ann. 
Bot., 1908, xxii, 489. 

AUPRECHT: Neue Arzneimittel, Speziahtaten und Vorschriften. Phann. Zentralhalle, 

1926, kvu, 552. 

BABCOCK, W W. : Spinal anesthesia. Amer. Jour. Surg , 1928, New Ser., v, 571. 

BAGOSLOWSKY: Ephedrine. Jahresb. Pharm , 1897, xxxii, 110. 

BAIN, W. A.: Action of Adrenaline and of Certain Drugs upon the Isolated Crustacean 

Heart. Quart. Jour. Exper. Physiol., 1929, six, 297. 
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L I B R A R Y 


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THDSNES, C.'H.: EphedrinvEpinephrine Antagonism. Proc. Soc. Exp. Biol. Med., 1928- 

1929, xxvi, 500. 

THIENES, C. H. AND HOCKEIT, A. J. : Cocaine Potentiation of Epinephrine and Ephedrine 
Action on Uterus and Intestine. Proc. Soc. Exp. BioL Med., 1927-1928, 
xxv, 793. 

THOMAS, W. S. : Ephedrin in Asthma. Amer. Jour. Med. Sc., 1926, clxxi, 719. 
THOMAS, W. S. : niniral Use of Ephedrine. N. Y. State Jour. Med., 1927, xxvii, 831. 
TDJSENEATJ, M.: L'adrenaline et ses groupements atomiques physiologiquement actifs. 
Paris Med., 1920, x, 390. 

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r, M.: La Pharmacologie en 1928 (Revue annueUe). Paris M6d., 1928, xviii, 

, M , Lfw, J. AND BOYESL, P. Sur quelques homologues de la nor-6ph6drine. 
Paris M6d., 1928, xviii, 553. 

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glattmuskligen Organe, nebst tlber die kombinierte Wurkung des Ephedrins 

' mit Atropin und Papaverian auf Froschoesophagus. Kyoto Igaku Zassi, 

1921, xviii, 411 (original in Japanese) ; 42 (abstract in German). 
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logical Standpoint. Jour. Amer. Pharm. Assoc., 1927, xvi, 294. 
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~S 1 

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YUAN, S. F.: Ma Huang. Allgemein. med. Zeit. chines. Reich., 1923, i, 13 (in Chinese). 


Absorption, 59, 94 

Action, mode of, 46 

Adams-Stokes 1 syndrome, use in, 75, 94 

Addison's disease, 43, 44, 55, 56, 72 

Administration, methods of, 62, 94 

Adrenaline, see epinephrine 

Alkaloids other than ephedrine in Ma 

Huang, 14, 93 
AUocain A, 91 
Allocam S, 91 

Arsphenamine reactions, use in, 81 
Asthma, pressor action in, 22 

treated with synthetic ephedrine, 84 

use in, 65, 94 
Asthmatol, 6, 11 

Atropine, 23, 24, 25, 27, 34, 35, 38, 41, 47, 
54, 57, 64, 70, 73, 78, 79 

Bile, effect on, 41 

Bladder, urinary, action on, 40, 53 

Blood cells, influence on, 42, 94 

Blood pressure, diminished effect on by 

repeated injections, 19 
effect upon, 17, 21, 93 
Blood sugar, influence on, 43, 94 
Blood vessels, action on, 29, 31 
Bronchi, action on, 40, 93 
Bronchitis and emphysema, use in, 70, 94 

Capillaries, action on, 31, 32 

Cardiac insufficiency, 64, 65, 73 

Cardiac output, effect on, 26 

Central nervous system, action on, 17, 45, 

46, 64, 94 

Chemical properties, 12, 13 
Cocaine, effect on pressor action, 50, 86 
Commercial development, recent, 11 
Contraindications, 65 
Council on Pharmacy and Chemistry, 

A. M. A., 7, 8 
Crabs' hearts, action on, 24 
Crop muscle of pigeon, action on, 35 

Diallylephedrine, 91 
o-Dihydroxyphenylethanolamine, 92 
Dosage, 62 
Dysmenorrhea, use in, 82, 94 

Electrocardiogram, effect on, 26, 28, 64, 75 
Ephedra, habitat, 7, 8 
species of, 4, 7 

species of, containing ephedrine, 8 
Ephedrine hydrochloride, 12 

export of, 11 
Ephedrine sulphate, 12 
Ephetonin, 15, 82 

Epinephrine, 3, 4, 6, 7, 13, 15, 16, 17, 18, 19, 
20, 21, 22, 24, 25, 26, 29, 30, 31, 32, 
33, 34, 35, 36, 37, 38, 39, 40, 44, 46, 
47, 48, 49, 50, 51, 52, 53, 55, 57, 58, 
64, 65, 66, 68, 74, 76, 79, 80, 81, 82, 
combined with ephedrine, 21, 68 
vs. ephednne, 18, 55, 59, 66, 76, 94 
Ergotamine, see ergotozLae 
Ergotozine, effect on pressor action, 48, 

Excretion, 59 

Formula of ephedrine, 13 
Frog's heart, action on, 23 

Gastric secretion, effect on, 41 
Graves' disease, 22, 65 

Habit formation, 65 

Hay fever, use in, 69, 94 

Heart, action on, 23, 27, 46, 93 

Hippuris, 4 

History, 4 

Hodgkm's disease, 43, 44 

Hypotension, use in, 72, 94 

Insulin, effect on pressor action, 51 
Intestinal secretion, effect on, 41 




Intestine, isolated, action on, 37 

large, action on, 37 

small, action on, 36 

small, plexus free, action on, 47 
Isoephedrine, IS 
ce-Isoephedrine, 91 
Isolation of ephedrine, 5, 7, 9 
Isomerism, 13 

Leprosy, use in, 81 

Lufinus albus, seedlings of, action on, 16 

Lymph, effect on, 42 

Ma Huang, 4, 5, 7, 8, 14, 41, 89, 90 

assay for ephedrine, 10 

export of, 11 

identification of, 8 

price of, 12 

Mammalian heart, action on, 25, 27 
Metabolism, influence on, 44, 94 
^>-Methoxyephedrine, 92 
co-Methoxymethylephedrine, 91 
^-Methoxy-norhoraoephedrine, 92 
m-Methoxy--oxyephedrine, 92 
Z-Methyl-ephedrine, 14, 90, 93 
Methylmydriatine, 14 
d-Methyl-pseudoephedrine, 14, 93 
Minimal lethal dose, 59 
Motor nerve, action on, 45 
Musculotropic action, 17, 47, 48, 49, 50, 52, 


Mydriatic action in different races, 78 
Mydriatine, 89 
Mydrin, 78 

Myoneural junctions, action on, 55, 93 
Myzedema, 22 

Nasal plethysmography, 77 
Nicotine, 34, 37, 52, 53 
Nor-ephedrine, 89, 93, 94 
Nor-homoephedrine, 90 
Nor-^-pseudoephedrine, 14, 89, 93 
Nose, use in, 62, 69, 76, 94 

(Esophagus, effect on, 35 
Ophthalmology, use in, 6, 62, 77, 94 
Optical isomers of ephedrine, action of, 87 

Parasympathetic system, action on, 53 
Pentsao Kang Mu, 4, 41 
Phenylethanolamine, 88 
0-Phenylethylamine, 88 
Phenylpropanolamine, ethers of, 91 
Physical properties, 12, 93 
Plexus of Auerbach, stimulation of, 52, 57 
Pneumonia, use in, 73 
Pseudoephedrine, 11, 14, 17, 23, 24, 40, 85, 

action of, 86 

vs. ephedrine, 86 
Pulse rate, effect on, 25, 27 
Pupil, action on, 33, 93 

denervated, diminished response in, 34 

Related compounds of ephedrine, 88 
Repeated administration in animals, 61 
Respiration, action on, 32 
Respiratory depression and failure, use in, 

Salivery secretion,, effect on, 40 

Scopolamine combined with ephedrine, 79 

Sea crab (Palaemon), action on, 16 

Sensory d[erve, action on, 46 

Serum albumin and globulin, effect on, 44 

Shock, use in, 74, 94 

Smooth muscle, action on, 33, 51, 93 

Snail's heart (Helix pomatia), action on, 24 

Spinal anesthesia, use in 71, 94 

Squid (Loligo peatii), action on, 16, 45, 61 

Stellate ganglia, action on, 25, 29, 57 

Stomach, action on, 35 

Suprarenal gland, stimulation, 55, 57 

Sweat glands, effect on, 41 

Sympathomimetic action, 3, 4, 15, 46, 47, 

48, 50, 52, 57 
Sympatol, 91 
Symptoms, toxic, in animals, 61 

untoward, 63, 94 
Synthesis, 14, 93 
Synthetic ephedrij^e, action of, 82 

clinical use of, 84, 93, 94 

vs. natural, 83 

Toad's heart, action on, 24 
Tolerance, development of, 62, 65 



Toxicity, 59, 94 

Turpentine reactions, use in, 81 
Turtle's heart, action on, 24 
Tyramine, SO, 91 

Ureter, action on, 39 
Urine, effect on, 42, 64 
Urticaria, use in, 80 
Uterus, action on, 39, 93 

Venous pressure, effect on, 23 
Voluntary muscle, action on, 46 

Whooping cough, use in, 70, 94 

Yield of ephedrine, 9 

seasonal variation, 10 
Yohimbine, effect on pressor action, 50 

Sans Tache 

Sans Tache 

IN THE "elder days of art" each artist or craftsman 
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